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Regulation of autophagosome biogenesis by OFD1‐mediated selective autophagy
Author(s) -
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
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2020105120
Subject(s) - autophagy , microbiology and biotechnology , autophagosome , atg8 , bag3 , autophagy related protein 13 , biogenesis , atg16l1 , biology , lysosome , mechanism (biology) , mitophagy , signal transduction , genetics , gene , biochemistry , apoptosis , mitogen activated protein kinase kinase , philosophy , protein kinase c , enzyme , epistemology
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.