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The LC3-conjugation machinery specifies the loading of RNA-binding proteins into extracellular vesicles.

  • Author(s): Leidal, Andrew M
  • Huang, Hector H
  • Marsh, Timothy
  • Solvik, Tina
  • Zhang, Dachuan
  • Ye, Jordan
  • Kai, FuiBoon
  • Goldsmith, Juliet
  • Liu, Jennifer Y
  • Huang, Yu-Hsin
  • Monkkonen, Teresa
  • Vlahakis, Ariadne
  • Huang, Eric J
  • Goodarzi, Hani
  • Yu, Li
  • Wiita, Arun P
  • Debnath, Jayanta
  • et al.

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.

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