title: ATG12-ATG3 interacts with Alix to promote basal autophagic flux and late endosome function.
abstract: The ubiquitin-like molecule ATG12 is required for the early steps of autophagy. Recently, we identified ATG3, the E2-like enzyme required for LC3 lipidation during autophagy, as an ATG12 conjugation target. Here, we demonstrate that cells lacking ATG12-ATG3 have impaired basal autophagic flux, accumulation of perinuclear late endosomes, and impaired endolysosomal trafficking. Furthermore, we identify an interaction between ATG12-ATG3 and the ESCRT-associated protein Alix (also known as PDCD6IP) and demonstrate that ATG12-ATG3 controls multiple Alix-dependent processes including late endosome distribution, exosome biogenesis and viral budding. Similar to ATG12-ATG3, Alix is functionally required for efficient basal, but not starvation-induced, autophagy. Overall, these results identify a link between the core autophagy and ESCRT machineries and uncover a role for ATG12-ATG3 in late endosome function that is distinct from the canonical role of either ATG in autophagosome formation.
authors: 1] Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA [2] Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, California 94143, USA.
authors: Lyndsay
authors: L
authors: Murrow
authors: Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA.
authors: Ritu
authors: R
authors: Malhotra
authors: 1] Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA [2] Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, California 94143, USA.
authors: Jayanta
authors: J
authors: Debnath
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001343:Autophagy / Q000235:genetics; D000071192:Autophagy-Related Protein 12; D000071183:Autophagy-Related Proteins; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000172:deficiency / Q000235:genetics*; D000097573:Red Fluorescent Protein
chemical_list: D000071192:Autophagy-Related Protein 12; D000071183:Autophagy-Related Proteins; D002135:Calcium-Binding Proteins; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins; D011506:Proteins; D044763:Ubiquitin-Conjugating Enzymes; D000097573:Red Fluorescent Protein; C491971:Atg12 protein, mouse; C492144:Pdcd6ip protein, mouse; C568853:Atg3 protein, mouse