Journal
NATURE CELL BIOLOGY
Volume 22, Issue 2, Pages 187-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41556-019-0450-y
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Funding
- NIH [CA201849, CA126792, CA213775, R00CA194077, R01CA240984, K08CA184116, AG057462]
- DOD BCRP [W81XWH-11-1-0130]
- Samuel Waxman Cancer Research Foundation
- UCSF QB3 Calico Longevity Fellowship
- Damon Runyon Cancer Research Foundation [DFS 14-15]
- Banting Postdoctoral Fellowship from the Government of Canada [201409BPF-335868]
- Cancer Research Society Scholarship for Next Generation of Scientists
- NSF [1650113, 1144247]
- Canadian Institutes of Health Research Post-doctoral Fellowship
- NRSA awards from the NCI [F31CA217015, F30CA224693]
- UCSF IRACDA Postdoctoral Fellowship [K12GM081266]
- NCI T32 training grant [T32CA108462]
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Traditionally viewed as an autodigestive pathway, autophagy also facilitates cellular secretion; however, the mechanisms underlying these processes remain unclear. Here, we demonstrate that components of the autophagy machinery specify secretion within extracellular vesicles (EVs). Using a proximity-dependent biotinylation proteomics strategy, we identify 200 putative targets of LC3-dependent secretion. This secretome consists of a highly interconnected network enriched in RNA-binding proteins (RBPs) and EV cargoes. Proteomic and RNA profiling of EVs identifies diverse RBPs and small non-coding RNAs requiring the LC3-conjugation machinery for packaging and secretion. Focusing on two RBPs, heterogeneous nuclear ribonucleoprotein K (HNRNPK) and scaffold-attachment factor B (SAFB), we demonstrate that these proteins interact with LC3 and are secreted within EVs enriched with lipidated LC3. Furthermore, their secretion requires the LC3-conjugation machinery, neutral sphingomyelinase 2 (nSMase2) and LC3-dependent recruitment of factor associated with nSMase2 activity (FAN). Hence, the LC3-conjugation pathway controls EV cargo loading and secretion. Leidal et al. show that the LC3-conjugation pathway, which is part of the autophagy machinery, controls extracellular vesicle cargo loading and secretion of RNA-binding proteins.
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