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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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Autores principales: Liang, Jingjing, Djurkovic, Marija A., Shtanko, Olena, Harty, Ronald N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9926251/
https://www.ncbi.nlm.nih.gov/pubmed/36598950
http://dx.doi.org/10.1073/pnas.2210690120
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author Liang, Jingjing
Djurkovic, Marija A.
Shtanko, Olena
Harty, Ronald N.
author_facet Liang, Jingjing
Djurkovic, Marija A.
Shtanko, Olena
Harty, Ronald N.
author_sort Liang, Jingjing
collection PubMed
description 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.
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spelling pubmed-99262512023-07-04 Chaperone-assisted selective autophagy targets filovirus VP40 as a client and restricts egress of virus particles Liang, Jingjing Djurkovic, Marija A. Shtanko, Olena Harty, Ronald N. Proc Natl Acad Sci U S A Biological Sciences 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. National Academy of Sciences 2023-01-04 2023-01-10 /pmc/articles/PMC9926251/ /pubmed/36598950 http://dx.doi.org/10.1073/pnas.2210690120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Liang, Jingjing
Djurkovic, Marija A.
Shtanko, Olena
Harty, Ronald N.
Chaperone-assisted selective autophagy targets filovirus VP40 as a client and restricts egress of virus particles
title Chaperone-assisted selective autophagy targets filovirus VP40 as a client and restricts egress of virus particles
title_full Chaperone-assisted selective autophagy targets filovirus VP40 as a client and restricts egress of virus particles
title_fullStr Chaperone-assisted selective autophagy targets filovirus VP40 as a client and restricts egress of virus particles
title_full_unstemmed Chaperone-assisted selective autophagy targets filovirus VP40 as a client and restricts egress of virus particles
title_short Chaperone-assisted selective autophagy targets filovirus VP40 as a client and restricts egress of virus particles
title_sort chaperone-assisted selective autophagy targets filovirus vp40 as a client and restricts egress of virus particles
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9926251/
https://www.ncbi.nlm.nih.gov/pubmed/36598950
http://dx.doi.org/10.1073/pnas.2210690120
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