Mary Wilson
Well-known member
January 4, 2023
120 (2) e2210690120
https://doi.org/10.1073/pnas.2210690120
Jingjing Liang, Marija A. Djurkovic, Olena Shtanko https://orcid.org/0000-0002-9848-8870, and Ronald N.Harty
Significance
Filoviruses EBOV and MARV are zoonotic, emerging pathogens that cause sporadic and global outbreaks of severe hemorrhagic fever. As filoviruses can establish persistent infections in immune-privileged sites inaccessible to antibody therapy, and their re-emergence can result in long-term sequelae and death, identifying virus–host interactions that contribute to their transmission and pathogenesis will reveal new opportunities and targets for antiviral development and intervention. Here, we describe how the mTORC1/CASA axis functions to regulate and restrict the egress of EBOV particles by targeting the main driver of filovirus budding—the VP40 matrix protein, which may represent a new host defense strategy in the ongoing arms race between virus and host.
Abstract
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.
https://www.pnas.org/doi/10.1073/pnas.2210690120
120 (2) e2210690120
https://doi.org/10.1073/pnas.2210690120
Jingjing Liang, Marija A. Djurkovic, Olena Shtanko https://orcid.org/0000-0002-9848-8870, and Ronald N.Harty
Significance
Filoviruses EBOV and MARV are zoonotic, emerging pathogens that cause sporadic and global outbreaks of severe hemorrhagic fever. As filoviruses can establish persistent infections in immune-privileged sites inaccessible to antibody therapy, and their re-emergence can result in long-term sequelae and death, identifying virus–host interactions that contribute to their transmission and pathogenesis will reveal new opportunities and targets for antiviral development and intervention. Here, we describe how the mTORC1/CASA axis functions to regulate and restrict the egress of EBOV particles by targeting the main driver of filovirus budding—the VP40 matrix protein, which may represent a new host defense strategy in the ongoing arms race between virus and host.
Abstract
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.
https://www.pnas.org/doi/10.1073/pnas.2210690120