Autophagy and autophagy-related genes (Atg) have been attributed prominent roles in tumorigenesis, tumor growth, and metastasis. Extracellular vesicles called exosomes are also implicated in cancer metastasis. Here, we demonstrate that exosome production is strongly reduced in cells lacking Atg5 and Atg16L1, but this is independent of Atg7 and canonical autophagy. Atg5 specifically decreases acidification of late endosomes where exosomes are produced, disrupting the acidifying VV-ATPase by removing a regulatory component, ATP6V1E1, into exosomes. The effect of Atg5 on exosome production promotes the migration and in vivo metastasis of orthotopic breast cancer cells. These findings uncover mechanisms controlling exosome release and identify means by which autophagy-related genes can contribute to metastasis in autophagy-independent pathways.
Mutations in proteins like FUS which cause Amyotrophic Lateral Sclerosis (ALS) result in the aberrant formation of stress granules while ALS-linked mutations in other proteins impede elimination of stress granules. Repeat expansions in C9ORF72, the major cause of ALS, reduce C9ORF72 levels but how this impacts stress granules is uncertain. Here, we demonstrate that C9ORF72 associates with the autophagy receptor p62 and controls elimination of stress granules by autophagy. This requires p62 to associate via the Tudor protein SMN with proteins, including FUS, that are symmetrically methylated on arginines. Mice lacking p62 accumulate arginine-methylated proteins and alterations in FUS-dependent splicing. Patients with C9ORF72 repeat expansions accumulate symmetric arginine dimethylated proteins which co-localize with p62. This suggests that C9ORF72 initiates a cascade of ALS-linked proteins (C9ORF72, p62, SMN, FUS) to recognize stress granules for degradation by autophagy and hallmarks of a defect in this process are observable in ALS patients.
Many cytoplasmic substrates degraded by autophagy have been identified; however, the impact of RNA degradation by autophagy remains uncertain. Retrotransposons comprise 40% of the human genome and are a major source of genetic variation among species, individuals and cells. Retrotransposons replicate via a copy-paste mechanism involving a cytoplasmic RNA intermediate. Here we report that autophagy degrades retrotransposon RNA from both long and short interspersed elements, preventing new retrotransposon insertions into the genome. Retrotransposon RNA localizes to RNA granules, whose selective degradation is facilitated by the autophagy receptors NDP52 and p62. Accordingly, NDP52 and p62 control retrotransposon insertion in the genome. Mice lacking a copy of Atg6/Beclin1, a gene critical for autophagy, also accumulate both retrotransposon RNA and genomic insertions. Thus, autophagy physiologically buffers genetic variegation by degrading retrotransposon RNA. This may contribute to the increased tumorigenesis occuring when autophagy is inhibited and suggest a role for autophagy in tempering evolutionary change.
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