Chaperone-assisted selective autophagy targets filovirus VP40 as a client and restricts egress of virus particles

The filovirus VP40 protein directs virion egress, which is regulated either positively or negatively by select VP40-host interactions. We demonstrate that host BAG3 and HSP70 recognize VP40 as a client and inhibit the egress of VP40 virus-like particles (VLPs) by promoting degradation of VP40 via Ch...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2023-01, Vol.120 (2), p.e2210690120-e2210690120
Main Authors: Liang, Jingjing, Djurkovic, Marija A, Shtanko, Olena, Harty, Ronald N
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - metabolism
Apoptosis Regulatory Proteins - metabolism
Autophagy
Biological Sciences
Ebolavirus - metabolism
Egress
Filoviridae
Hsp70 protein
Humans
Macroautophagy
Pharmacology
Rapamycin
Signal Transduction
TOR protein
Viral Matrix Proteins - metabolism
Virion - metabolism
Virions
Virus-like particles
Viruses
VP40 protein
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Summary:The filovirus VP40 protein directs virion egress, which is regulated either positively or negatively by select VP40-host interactions. We demonstrate that host BAG3 and HSP70 recognize VP40 as a client and inhibit the egress of VP40 virus-like particles (VLPs) by promoting degradation of VP40 via Chaperone-assisted selective autophagy (CASA). Pharmacological inhibition of either the early stage formation of the VP40/BAG3/HSP70 tripartite complex, or late stage formation of autolysosomes, rescued VP40 VLP egress back to WT levels. The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of autophagy, and we found that surface expression of EBOV GP on either VLPs or an infectious VSV recombinant virus, activated mTORC1. Notably, pharmacological suppression of mTORC1 signaling by rapamycin activated CASA in a BAG3-dependent manner to restrict the egress of both VLPs and infectious EBOV in Huh7 cells. In sum, our findings highlight the involvement of the mTORC1/CASA axis in regulating filovirus egress.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2210690120