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The LC3-conjugation machinery specifies the loading of RNA-binding proteins into extracellular vesicles
Open accessAbstract
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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Metadata
- Authors
- Leidal, A. M., Huang, H. H., Marsh, T., Solvik, T., Zhang, D., Ye, J., Kai, F., Goldsmith, J., Liu, J. Y., Huang, Y.-H., Monkkonen, T., Vlahakis, A., Huang, E. J., Goodarzi, H., Yu, L., Wiita, A. P., & Debnath, J.
- Venue
- Nature Cell Biology
- Published
- 2020-01-13
- Volume
- 22
- Issue
- 2
- Pages
- 187-199
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W3000522739
- Cited by
- 486
- References
- 82
- FWCI
- 19.29
- Type
- journal article
- Language
- en
- Open access
- green
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- Leidal, A. M., Huang, H. H., Marsh, T., Solvik, T., Zhang, D., Ye, J., Kai, F., Goldsmith, J., Liu, J. Y., Huang, Y.-H., Monkkonen, T., Vlahakis, A., Huang, E. J., Goodarzi, H., Yu, L., Wiita, A. P., & Debnath, J. (2020). The LC3-conjugation machinery specifies the loading of RNA-binding proteins into extracellular vesicles. Nature Cell Biology. https://doi.org/10.1038/s41556-019-0450-y
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