ATG12-ATG3 interacts with Alix to promote basal autophagic flux and late endosome function

Lyndsay Murrow; Ritu Malhotra; Jayanta Debnath

doi:10.1038/ncb3112

ATG12-ATG3 interacts with Alix to promote basal autophagic flux and late endosome function

Nat Cell Biol. 2015 Mar;17(3):300-10. doi: 10.1038/ncb3112. Epub 2015 Feb 16.

Authors

Lyndsay Murrow¹, Ritu Malhotra², Jayanta Debnath¹

Affiliations

¹ 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.
² Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA.

PMID: 25686249
PMCID: PMC4344874
DOI: 10.1038/ncb3112

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
Autophagy / genetics
Autophagy-Related Protein 12
Autophagy-Related Proteins
Calcium Signaling
Calcium-Binding Proteins / genetics*
Calcium-Binding Proteins / metabolism
Endosomes / metabolism*
Fibroblasts / cytology
Fibroblasts / metabolism*
Gene Deletion
Gene Expression Regulation
Genes, Reporter
Green Fluorescent Proteins / genetics
Green Fluorescent Proteins / metabolism
Luminescent Proteins / genetics
Luminescent Proteins / metabolism
Mice
Molecular Sequence Data
Proteins / genetics*
Proteins / metabolism
Red Fluorescent Protein
Ubiquitin-Conjugating Enzymes / deficiency
Ubiquitin-Conjugating Enzymes / genetics*

Substances

Atg12 protein, mouse
Autophagy-Related Protein 12
Autophagy-Related Proteins
Calcium-Binding Proteins
Luminescent Proteins
Pdcd6ip protein, mouse
Proteins
Green Fluorescent Proteins
Ubiquitin-Conjugating Enzymes
Atg3 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding