Regulation of autophagosome biogenesis by OFD1‐mediated selective autophagy
Abstract Autophagy is a lysosome‐dependent degradation pathway essential to maintain cellular homeostasis. Therefore, either defective or excessive autophagy may be detrimental for cells and tissues. The past decade was characterized by significant advances in molecular dissection of stimulatory aut...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Morleo, Manuela [verfasserIn] Brillante, Simona [verfasserIn] Formisano, Umberto [verfasserIn] Ferrante, Luigi [verfasserIn] Carbone, Fabrizia [verfasserIn] Iaconis, Daniela [verfasserIn] Palma, Alessandro [verfasserIn] Buonomo, Viviana [verfasserIn] Maione, Angela Serena [verfasserIn] Grumati, Paolo [verfasserIn] Settembre, Carmine [verfasserIn] Franco, Brunella [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2020 |
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| Schlagwörter: |
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| Anmerkung: |
© The Author(s) 2020 |
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| Übergeordnetes Werk: |
Enthalten in: The EMBO Journal - Nature Publishing Group UK, 2023, 40(2020), 4 vom: 28. Dez. |
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| Übergeordnetes Werk: |
volume:40 ; year:2020 ; number:4 ; day:28 ; month:12 |
| Links: |
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| DOI / URN: |
10.15252/embj.2020105120 |
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| Katalog-ID: |
SPR058110941 |
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| 245 | 1 | 0 | |a Regulation of autophagosome biogenesis by OFD1‐mediated selective autophagy |
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| 520 | |a Abstract Autophagy is a lysosome‐dependent degradation pathway essential to maintain cellular homeostasis. Therefore, either defective or excessive autophagy may be detrimental for cells and tissues. The past decade was characterized by significant advances in molecular dissection of stimulatory autophagy inputs; however, our understanding of the mechanisms that restrain autophagy is far from complete. Here, we describe a negative feedback mechanism that limits autophagosome biogenesis based on the selective autophagy‐mediated degradation of ATG13, a component of the ULK1 autophagy initiation complex. We demonstrate that the centrosomal protein OFD1 acts as bona fide autophagy receptor for ATG13 via direct interaction with the Atg8/LC3/GABARAP family of proteins. We also show that patients with Oral‐Facial‐Digital type I syndrome, caused by mutations in the OFD1 gene, display excessive autophagy and that genetic inhibition of autophagy in a mouse model of the disease, significantly ameliorates polycystic kidney, a clinical manifestation of the disorder. Collectively, our data report the discovery of an autophagy self‐regulated mechanism and implicate dysregulated autophagy in the pathogenesis of renal cystic disease in mammals. | ||
| 520 | |a SYNOPSIS The molecular pathways inhibiting autophagy are still ill‐defined. This study shows that centrosomal protein OFD1 restrains autophagy and prevents pathogenesis of renal cystic disease in mammals through selective autophagy‐mediated degradation of the ULK1 complex component ATG13. Oral‐facial‐digital syndrome 1 (OFD1) protein is a bona fide autophagy receptor for ATG13 that interacts with Atg8/LC3/GABARAP‐family of proteins.OFD1 promotes ATG13 degradation via selective autophagy.Loss of OFD1 increases the stability of the ULK1 complex and enhances autophagy.Enhanced autophagy contributes to renal cystic disease in a mouse model of Oral‐Facial‐Digital type I syndrome. | ||
| 520 | |a Graphical Abstract Centrosomal protein OFD1 restrains autophagy and prevents pathogenesis of renal cystic disease in mammals through selective autophagy‐mediated degradation of the ULK1‐complex component ATG13. | ||
| 650 | 4 | |a autophagy receptor |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a OFD1 |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a polycystic kidney |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a selective autophagy |7 (dpeaa)DE-He213 | |
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| 700 | 1 | |a Palma, Alessandro |e verfasserin |4 aut | |
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| 700 | 1 | |a Franco, Brunella |e verfasserin |0 (orcid)0000-0001-5588-4569 |4 aut | |
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10.15252/embj.2020105120 doi (DE-627)SPR058110941 (SPR)embj.2020105120-e DE-627 ger DE-627 rakwb eng Morleo, Manuela verfasserin (orcid)0000-0002-7553-3245 aut Regulation of autophagosome biogenesis by OFD1‐mediated selective autophagy 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 Abstract Autophagy is a lysosome‐dependent degradation pathway essential to maintain cellular homeostasis. Therefore, either defective or excessive autophagy may be detrimental for cells and tissues. The past decade was characterized by significant advances in molecular dissection of stimulatory autophagy inputs; however, our understanding of the mechanisms that restrain autophagy is far from complete. Here, we describe a negative feedback mechanism that limits autophagosome biogenesis based on the selective autophagy‐mediated degradation of ATG13, a component of the ULK1 autophagy initiation complex. We demonstrate that the centrosomal protein OFD1 acts as bona fide autophagy receptor for ATG13 via direct interaction with the Atg8/LC3/GABARAP family of proteins. We also show that patients with Oral‐Facial‐Digital type I syndrome, caused by mutations in the OFD1 gene, display excessive autophagy and that genetic inhibition of autophagy in a mouse model of the disease, significantly ameliorates polycystic kidney, a clinical manifestation of the disorder. Collectively, our data report the discovery of an autophagy self‐regulated mechanism and implicate dysregulated autophagy in the pathogenesis of renal cystic disease in mammals. SYNOPSIS The molecular pathways inhibiting autophagy are still ill‐defined. This study shows that centrosomal protein OFD1 restrains autophagy and prevents pathogenesis of renal cystic disease in mammals through selective autophagy‐mediated degradation of the ULK1 complex component ATG13. Oral‐facial‐digital syndrome 1 (OFD1) protein is a bona fide autophagy receptor for ATG13 that interacts with Atg8/LC3/GABARAP‐family of proteins.OFD1 promotes ATG13 degradation via selective autophagy.Loss of OFD1 increases the stability of the ULK1 complex and enhances autophagy.Enhanced autophagy contributes to renal cystic disease in a mouse model of Oral‐Facial‐Digital type I syndrome. Graphical Abstract Centrosomal protein OFD1 restrains autophagy and prevents pathogenesis of renal cystic disease in mammals through selective autophagy‐mediated degradation of the ULK1‐complex component ATG13. autophagy receptor (dpeaa)DE-He213 OFD1 (dpeaa)DE-He213 polycystic kidney (dpeaa)DE-He213 selective autophagy (dpeaa)DE-He213 Brillante, Simona verfasserin aut Formisano, Umberto verfasserin aut Ferrante, Luigi verfasserin aut Carbone, Fabrizia verfasserin aut Iaconis, Daniela verfasserin aut Palma, Alessandro verfasserin aut Buonomo, Viviana verfasserin aut Maione, Angela Serena verfasserin aut Grumati, Paolo verfasserin aut Settembre, Carmine verfasserin (orcid)0000-0002-5829-8589 aut Franco, Brunella verfasserin (orcid)0000-0001-5588-4569 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 40(2020), 4 vom: 28. Dez. (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:40 year:2020 number:4 day:28 month:12 https://dx.doi.org/10.15252/embj.2020105120 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 40 2020 4 28 12 |
| spelling |
10.15252/embj.2020105120 doi (DE-627)SPR058110941 (SPR)embj.2020105120-e DE-627 ger DE-627 rakwb eng Morleo, Manuela verfasserin (orcid)0000-0002-7553-3245 aut Regulation of autophagosome biogenesis by OFD1‐mediated selective autophagy 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 Abstract Autophagy is a lysosome‐dependent degradation pathway essential to maintain cellular homeostasis. Therefore, either defective or excessive autophagy may be detrimental for cells and tissues. The past decade was characterized by significant advances in molecular dissection of stimulatory autophagy inputs; however, our understanding of the mechanisms that restrain autophagy is far from complete. Here, we describe a negative feedback mechanism that limits autophagosome biogenesis based on the selective autophagy‐mediated degradation of ATG13, a component of the ULK1 autophagy initiation complex. We demonstrate that the centrosomal protein OFD1 acts as bona fide autophagy receptor for ATG13 via direct interaction with the Atg8/LC3/GABARAP family of proteins. We also show that patients with Oral‐Facial‐Digital type I syndrome, caused by mutations in the OFD1 gene, display excessive autophagy and that genetic inhibition of autophagy in a mouse model of the disease, significantly ameliorates polycystic kidney, a clinical manifestation of the disorder. Collectively, our data report the discovery of an autophagy self‐regulated mechanism and implicate dysregulated autophagy in the pathogenesis of renal cystic disease in mammals. SYNOPSIS The molecular pathways inhibiting autophagy are still ill‐defined. This study shows that centrosomal protein OFD1 restrains autophagy and prevents pathogenesis of renal cystic disease in mammals through selective autophagy‐mediated degradation of the ULK1 complex component ATG13. Oral‐facial‐digital syndrome 1 (OFD1) protein is a bona fide autophagy receptor for ATG13 that interacts with Atg8/LC3/GABARAP‐family of proteins.OFD1 promotes ATG13 degradation via selective autophagy.Loss of OFD1 increases the stability of the ULK1 complex and enhances autophagy.Enhanced autophagy contributes to renal cystic disease in a mouse model of Oral‐Facial‐Digital type I syndrome. Graphical Abstract Centrosomal protein OFD1 restrains autophagy and prevents pathogenesis of renal cystic disease in mammals through selective autophagy‐mediated degradation of the ULK1‐complex component ATG13. autophagy receptor (dpeaa)DE-He213 OFD1 (dpeaa)DE-He213 polycystic kidney (dpeaa)DE-He213 selective autophagy (dpeaa)DE-He213 Brillante, Simona verfasserin aut Formisano, Umberto verfasserin aut Ferrante, Luigi verfasserin aut Carbone, Fabrizia verfasserin aut Iaconis, Daniela verfasserin aut Palma, Alessandro verfasserin aut Buonomo, Viviana verfasserin aut Maione, Angela Serena verfasserin aut Grumati, Paolo verfasserin aut Settembre, Carmine verfasserin (orcid)0000-0002-5829-8589 aut Franco, Brunella verfasserin (orcid)0000-0001-5588-4569 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 40(2020), 4 vom: 28. Dez. (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:40 year:2020 number:4 day:28 month:12 https://dx.doi.org/10.15252/embj.2020105120 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 40 2020 4 28 12 |
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10.15252/embj.2020105120 doi (DE-627)SPR058110941 (SPR)embj.2020105120-e DE-627 ger DE-627 rakwb eng Morleo, Manuela verfasserin (orcid)0000-0002-7553-3245 aut Regulation of autophagosome biogenesis by OFD1‐mediated selective autophagy 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 Abstract Autophagy is a lysosome‐dependent degradation pathway essential to maintain cellular homeostasis. Therefore, either defective or excessive autophagy may be detrimental for cells and tissues. The past decade was characterized by significant advances in molecular dissection of stimulatory autophagy inputs; however, our understanding of the mechanisms that restrain autophagy is far from complete. Here, we describe a negative feedback mechanism that limits autophagosome biogenesis based on the selective autophagy‐mediated degradation of ATG13, a component of the ULK1 autophagy initiation complex. We demonstrate that the centrosomal protein OFD1 acts as bona fide autophagy receptor for ATG13 via direct interaction with the Atg8/LC3/GABARAP family of proteins. We also show that patients with Oral‐Facial‐Digital type I syndrome, caused by mutations in the OFD1 gene, display excessive autophagy and that genetic inhibition of autophagy in a mouse model of the disease, significantly ameliorates polycystic kidney, a clinical manifestation of the disorder. Collectively, our data report the discovery of an autophagy self‐regulated mechanism and implicate dysregulated autophagy in the pathogenesis of renal cystic disease in mammals. SYNOPSIS The molecular pathways inhibiting autophagy are still ill‐defined. This study shows that centrosomal protein OFD1 restrains autophagy and prevents pathogenesis of renal cystic disease in mammals through selective autophagy‐mediated degradation of the ULK1 complex component ATG13. Oral‐facial‐digital syndrome 1 (OFD1) protein is a bona fide autophagy receptor for ATG13 that interacts with Atg8/LC3/GABARAP‐family of proteins.OFD1 promotes ATG13 degradation via selective autophagy.Loss of OFD1 increases the stability of the ULK1 complex and enhances autophagy.Enhanced autophagy contributes to renal cystic disease in a mouse model of Oral‐Facial‐Digital type I syndrome. Graphical Abstract Centrosomal protein OFD1 restrains autophagy and prevents pathogenesis of renal cystic disease in mammals through selective autophagy‐mediated degradation of the ULK1‐complex component ATG13. autophagy receptor (dpeaa)DE-He213 OFD1 (dpeaa)DE-He213 polycystic kidney (dpeaa)DE-He213 selective autophagy (dpeaa)DE-He213 Brillante, Simona verfasserin aut Formisano, Umberto verfasserin aut Ferrante, Luigi verfasserin aut Carbone, Fabrizia verfasserin aut Iaconis, Daniela verfasserin aut Palma, Alessandro verfasserin aut Buonomo, Viviana verfasserin aut Maione, Angela Serena verfasserin aut Grumati, Paolo verfasserin aut Settembre, Carmine verfasserin (orcid)0000-0002-5829-8589 aut Franco, Brunella verfasserin (orcid)0000-0001-5588-4569 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 40(2020), 4 vom: 28. Dez. (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:40 year:2020 number:4 day:28 month:12 https://dx.doi.org/10.15252/embj.2020105120 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 40 2020 4 28 12 |
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10.15252/embj.2020105120 doi (DE-627)SPR058110941 (SPR)embj.2020105120-e DE-627 ger DE-627 rakwb eng Morleo, Manuela verfasserin (orcid)0000-0002-7553-3245 aut Regulation of autophagosome biogenesis by OFD1‐mediated selective autophagy 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 Abstract Autophagy is a lysosome‐dependent degradation pathway essential to maintain cellular homeostasis. Therefore, either defective or excessive autophagy may be detrimental for cells and tissues. The past decade was characterized by significant advances in molecular dissection of stimulatory autophagy inputs; however, our understanding of the mechanisms that restrain autophagy is far from complete. Here, we describe a negative feedback mechanism that limits autophagosome biogenesis based on the selective autophagy‐mediated degradation of ATG13, a component of the ULK1 autophagy initiation complex. We demonstrate that the centrosomal protein OFD1 acts as bona fide autophagy receptor for ATG13 via direct interaction with the Atg8/LC3/GABARAP family of proteins. We also show that patients with Oral‐Facial‐Digital type I syndrome, caused by mutations in the OFD1 gene, display excessive autophagy and that genetic inhibition of autophagy in a mouse model of the disease, significantly ameliorates polycystic kidney, a clinical manifestation of the disorder. Collectively, our data report the discovery of an autophagy self‐regulated mechanism and implicate dysregulated autophagy in the pathogenesis of renal cystic disease in mammals. SYNOPSIS The molecular pathways inhibiting autophagy are still ill‐defined. This study shows that centrosomal protein OFD1 restrains autophagy and prevents pathogenesis of renal cystic disease in mammals through selective autophagy‐mediated degradation of the ULK1 complex component ATG13. Oral‐facial‐digital syndrome 1 (OFD1) protein is a bona fide autophagy receptor for ATG13 that interacts with Atg8/LC3/GABARAP‐family of proteins.OFD1 promotes ATG13 degradation via selective autophagy.Loss of OFD1 increases the stability of the ULK1 complex and enhances autophagy.Enhanced autophagy contributes to renal cystic disease in a mouse model of Oral‐Facial‐Digital type I syndrome. Graphical Abstract Centrosomal protein OFD1 restrains autophagy and prevents pathogenesis of renal cystic disease in mammals through selective autophagy‐mediated degradation of the ULK1‐complex component ATG13. autophagy receptor (dpeaa)DE-He213 OFD1 (dpeaa)DE-He213 polycystic kidney (dpeaa)DE-He213 selective autophagy (dpeaa)DE-He213 Brillante, Simona verfasserin aut Formisano, Umberto verfasserin aut Ferrante, Luigi verfasserin aut Carbone, Fabrizia verfasserin aut Iaconis, Daniela verfasserin aut Palma, Alessandro verfasserin aut Buonomo, Viviana verfasserin aut Maione, Angela Serena verfasserin aut Grumati, Paolo verfasserin aut Settembre, Carmine verfasserin (orcid)0000-0002-5829-8589 aut Franco, Brunella verfasserin (orcid)0000-0001-5588-4569 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 40(2020), 4 vom: 28. Dez. (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:40 year:2020 number:4 day:28 month:12 https://dx.doi.org/10.15252/embj.2020105120 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 40 2020 4 28 12 |
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10.15252/embj.2020105120 doi (DE-627)SPR058110941 (SPR)embj.2020105120-e DE-627 ger DE-627 rakwb eng Morleo, Manuela verfasserin (orcid)0000-0002-7553-3245 aut Regulation of autophagosome biogenesis by OFD1‐mediated selective autophagy 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 Abstract Autophagy is a lysosome‐dependent degradation pathway essential to maintain cellular homeostasis. Therefore, either defective or excessive autophagy may be detrimental for cells and tissues. The past decade was characterized by significant advances in molecular dissection of stimulatory autophagy inputs; however, our understanding of the mechanisms that restrain autophagy is far from complete. Here, we describe a negative feedback mechanism that limits autophagosome biogenesis based on the selective autophagy‐mediated degradation of ATG13, a component of the ULK1 autophagy initiation complex. We demonstrate that the centrosomal protein OFD1 acts as bona fide autophagy receptor for ATG13 via direct interaction with the Atg8/LC3/GABARAP family of proteins. We also show that patients with Oral‐Facial‐Digital type I syndrome, caused by mutations in the OFD1 gene, display excessive autophagy and that genetic inhibition of autophagy in a mouse model of the disease, significantly ameliorates polycystic kidney, a clinical manifestation of the disorder. Collectively, our data report the discovery of an autophagy self‐regulated mechanism and implicate dysregulated autophagy in the pathogenesis of renal cystic disease in mammals. SYNOPSIS The molecular pathways inhibiting autophagy are still ill‐defined. This study shows that centrosomal protein OFD1 restrains autophagy and prevents pathogenesis of renal cystic disease in mammals through selective autophagy‐mediated degradation of the ULK1 complex component ATG13. Oral‐facial‐digital syndrome 1 (OFD1) protein is a bona fide autophagy receptor for ATG13 that interacts with Atg8/LC3/GABARAP‐family of proteins.OFD1 promotes ATG13 degradation via selective autophagy.Loss of OFD1 increases the stability of the ULK1 complex and enhances autophagy.Enhanced autophagy contributes to renal cystic disease in a mouse model of Oral‐Facial‐Digital type I syndrome. Graphical Abstract Centrosomal protein OFD1 restrains autophagy and prevents pathogenesis of renal cystic disease in mammals through selective autophagy‐mediated degradation of the ULK1‐complex component ATG13. autophagy receptor (dpeaa)DE-He213 OFD1 (dpeaa)DE-He213 polycystic kidney (dpeaa)DE-He213 selective autophagy (dpeaa)DE-He213 Brillante, Simona verfasserin aut Formisano, Umberto verfasserin aut Ferrante, Luigi verfasserin aut Carbone, Fabrizia verfasserin aut Iaconis, Daniela verfasserin aut Palma, Alessandro verfasserin aut Buonomo, Viviana verfasserin aut Maione, Angela Serena verfasserin aut Grumati, Paolo verfasserin aut Settembre, Carmine verfasserin (orcid)0000-0002-5829-8589 aut Franco, Brunella verfasserin (orcid)0000-0001-5588-4569 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 40(2020), 4 vom: 28. Dez. (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:40 year:2020 number:4 day:28 month:12 https://dx.doi.org/10.15252/embj.2020105120 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 40 2020 4 28 12 |
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Enthalten in The EMBO Journal 40(2020), 4 vom: 28. Dez. volume:40 year:2020 number:4 day:28 month:12 |
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Morleo, Manuela @@aut@@ Brillante, Simona @@aut@@ Formisano, Umberto @@aut@@ Ferrante, Luigi @@aut@@ Carbone, Fabrizia @@aut@@ Iaconis, Daniela @@aut@@ Palma, Alessandro @@aut@@ Buonomo, Viviana @@aut@@ Maione, Angela Serena @@aut@@ Grumati, Paolo @@aut@@ Settembre, Carmine @@aut@@ Franco, Brunella @@aut@@ |
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Therefore, either defective or excessive autophagy may be detrimental for cells and tissues. The past decade was characterized by significant advances in molecular dissection of stimulatory autophagy inputs; however, our understanding of the mechanisms that restrain autophagy is far from complete. Here, we describe a negative feedback mechanism that limits autophagosome biogenesis based on the selective autophagy‐mediated degradation of ATG13, a component of the ULK1 autophagy initiation complex. We demonstrate that the centrosomal protein OFD1 acts as bona fide autophagy receptor for ATG13 via direct interaction with the Atg8/LC3/GABARAP family of proteins. We also show that patients with Oral‐Facial‐Digital type I syndrome, caused by mutations in the OFD1 gene, display excessive autophagy and that genetic inhibition of autophagy in a mouse model of the disease, significantly ameliorates polycystic kidney, a clinical manifestation of the disorder. Collectively, our data report the discovery of an autophagy self‐regulated mechanism and implicate dysregulated autophagy in the pathogenesis of renal cystic disease in mammals.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">SYNOPSIS The molecular pathways inhibiting autophagy are still ill‐defined. This study shows that centrosomal protein OFD1 restrains autophagy and prevents pathogenesis of renal cystic disease in mammals through selective autophagy‐mediated degradation of the ULK1 complex component ATG13. Oral‐facial‐digital syndrome 1 (OFD1) protein is a bona fide autophagy receptor for ATG13 that interacts with Atg8/LC3/GABARAP‐family of proteins.OFD1 promotes ATG13 degradation via selective autophagy.Loss of OFD1 increases the stability of the ULK1 complex and enhances autophagy.Enhanced autophagy contributes to renal cystic disease in a mouse model of Oral‐Facial‐Digital type I syndrome.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Graphical Abstract Centrosomal protein OFD1 restrains autophagy and prevents pathogenesis of renal cystic disease in mammals through selective autophagy‐mediated degradation of the ULK1‐complex component ATG13.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">autophagy receptor</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">OFD1</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">polycystic kidney</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">selective autophagy</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Brillante, Simona</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Formisano, Umberto</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Ferrante, Luigi</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Carbone, Fabrizia</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Iaconis, Daniela</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Palma, Alessandro</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Buonomo, Viviana</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Maione, Angela Serena</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Grumati, Paolo</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Settembre, Carmine</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0002-5829-8589</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Franco, Brunella</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0001-5588-4569</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="t">The EMBO Journal</subfield><subfield code="d">Nature Publishing Group UK, 2023</subfield><subfield code="g">40(2020), 4 vom: 28. 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Morleo, Manuela |
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Regulation of autophagosome biogenesis by OFD1‐mediated selective autophagy autophagy receptor (dpeaa)DE-He213 OFD1 (dpeaa)DE-He213 polycystic kidney (dpeaa)DE-He213 selective autophagy (dpeaa)DE-He213 |
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Morleo, Manuela Brillante, Simona Formisano, Umberto Ferrante, Luigi Carbone, Fabrizia Iaconis, Daniela Palma, Alessandro Buonomo, Viviana Maione, Angela Serena Grumati, Paolo Settembre, Carmine Franco, Brunella |
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Elektronische Aufsätze |
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Morleo, Manuela |
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10.15252/embj.2020105120 |
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regulation of autophagosome biogenesis by ofd1‐mediated selective autophagy |
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Regulation of autophagosome biogenesis by OFD1‐mediated selective autophagy |
| abstract |
Abstract Autophagy is a lysosome‐dependent degradation pathway essential to maintain cellular homeostasis. Therefore, either defective or excessive autophagy may be detrimental for cells and tissues. The past decade was characterized by significant advances in molecular dissection of stimulatory autophagy inputs; however, our understanding of the mechanisms that restrain autophagy is far from complete. Here, we describe a negative feedback mechanism that limits autophagosome biogenesis based on the selective autophagy‐mediated degradation of ATG13, a component of the ULK1 autophagy initiation complex. We demonstrate that the centrosomal protein OFD1 acts as bona fide autophagy receptor for ATG13 via direct interaction with the Atg8/LC3/GABARAP family of proteins. We also show that patients with Oral‐Facial‐Digital type I syndrome, caused by mutations in the OFD1 gene, display excessive autophagy and that genetic inhibition of autophagy in a mouse model of the disease, significantly ameliorates polycystic kidney, a clinical manifestation of the disorder. Collectively, our data report the discovery of an autophagy self‐regulated mechanism and implicate dysregulated autophagy in the pathogenesis of renal cystic disease in mammals. SYNOPSIS The molecular pathways inhibiting autophagy are still ill‐defined. This study shows that centrosomal protein OFD1 restrains autophagy and prevents pathogenesis of renal cystic disease in mammals through selective autophagy‐mediated degradation of the ULK1 complex component ATG13. Oral‐facial‐digital syndrome 1 (OFD1) protein is a bona fide autophagy receptor for ATG13 that interacts with Atg8/LC3/GABARAP‐family of proteins.OFD1 promotes ATG13 degradation via selective autophagy.Loss of OFD1 increases the stability of the ULK1 complex and enhances autophagy.Enhanced autophagy contributes to renal cystic disease in a mouse model of Oral‐Facial‐Digital type I syndrome. Graphical Abstract Centrosomal protein OFD1 restrains autophagy and prevents pathogenesis of renal cystic disease in mammals through selective autophagy‐mediated degradation of the ULK1‐complex component ATG13. © The Author(s) 2020 |
| abstractGer |
Abstract Autophagy is a lysosome‐dependent degradation pathway essential to maintain cellular homeostasis. Therefore, either defective or excessive autophagy may be detrimental for cells and tissues. The past decade was characterized by significant advances in molecular dissection of stimulatory autophagy inputs; however, our understanding of the mechanisms that restrain autophagy is far from complete. Here, we describe a negative feedback mechanism that limits autophagosome biogenesis based on the selective autophagy‐mediated degradation of ATG13, a component of the ULK1 autophagy initiation complex. We demonstrate that the centrosomal protein OFD1 acts as bona fide autophagy receptor for ATG13 via direct interaction with the Atg8/LC3/GABARAP family of proteins. We also show that patients with Oral‐Facial‐Digital type I syndrome, caused by mutations in the OFD1 gene, display excessive autophagy and that genetic inhibition of autophagy in a mouse model of the disease, significantly ameliorates polycystic kidney, a clinical manifestation of the disorder. Collectively, our data report the discovery of an autophagy self‐regulated mechanism and implicate dysregulated autophagy in the pathogenesis of renal cystic disease in mammals. SYNOPSIS The molecular pathways inhibiting autophagy are still ill‐defined. This study shows that centrosomal protein OFD1 restrains autophagy and prevents pathogenesis of renal cystic disease in mammals through selective autophagy‐mediated degradation of the ULK1 complex component ATG13. Oral‐facial‐digital syndrome 1 (OFD1) protein is a bona fide autophagy receptor for ATG13 that interacts with Atg8/LC3/GABARAP‐family of proteins.OFD1 promotes ATG13 degradation via selective autophagy.Loss of OFD1 increases the stability of the ULK1 complex and enhances autophagy.Enhanced autophagy contributes to renal cystic disease in a mouse model of Oral‐Facial‐Digital type I syndrome. Graphical Abstract Centrosomal protein OFD1 restrains autophagy and prevents pathogenesis of renal cystic disease in mammals through selective autophagy‐mediated degradation of the ULK1‐complex component ATG13. © The Author(s) 2020 |
| abstract_unstemmed |
Abstract Autophagy is a lysosome‐dependent degradation pathway essential to maintain cellular homeostasis. Therefore, either defective or excessive autophagy may be detrimental for cells and tissues. The past decade was characterized by significant advances in molecular dissection of stimulatory autophagy inputs; however, our understanding of the mechanisms that restrain autophagy is far from complete. Here, we describe a negative feedback mechanism that limits autophagosome biogenesis based on the selective autophagy‐mediated degradation of ATG13, a component of the ULK1 autophagy initiation complex. We demonstrate that the centrosomal protein OFD1 acts as bona fide autophagy receptor for ATG13 via direct interaction with the Atg8/LC3/GABARAP family of proteins. We also show that patients with Oral‐Facial‐Digital type I syndrome, caused by mutations in the OFD1 gene, display excessive autophagy and that genetic inhibition of autophagy in a mouse model of the disease, significantly ameliorates polycystic kidney, a clinical manifestation of the disorder. Collectively, our data report the discovery of an autophagy self‐regulated mechanism and implicate dysregulated autophagy in the pathogenesis of renal cystic disease in mammals. SYNOPSIS The molecular pathways inhibiting autophagy are still ill‐defined. This study shows that centrosomal protein OFD1 restrains autophagy and prevents pathogenesis of renal cystic disease in mammals through selective autophagy‐mediated degradation of the ULK1 complex component ATG13. Oral‐facial‐digital syndrome 1 (OFD1) protein is a bona fide autophagy receptor for ATG13 that interacts with Atg8/LC3/GABARAP‐family of proteins.OFD1 promotes ATG13 degradation via selective autophagy.Loss of OFD1 increases the stability of the ULK1 complex and enhances autophagy.Enhanced autophagy contributes to renal cystic disease in a mouse model of Oral‐Facial‐Digital type I syndrome. Graphical Abstract Centrosomal protein OFD1 restrains autophagy and prevents pathogenesis of renal cystic disease in mammals through selective autophagy‐mediated degradation of the ULK1‐complex component ATG13. © The Author(s) 2020 |
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Regulation of autophagosome biogenesis by OFD1‐mediated selective autophagy |
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| score |
7.4017944 |