Peroxisomes support human herpesvirus 8 latency by stabilizing the viral oncogenic protein vFLIP via the MAVS-TRAF complex
Year: 2018
Type: article
Abstract: Human herpesvirus 8 (HHV-8) is causally related to human malignancies.HHV-8 latent viral FLICE-inhibitory protein (vFLIP) is a viral oncoprotein that is linked to pathogenesis, but how its expression is regulated is largely unknown.In an attempt to understand the role of the mitochondrial antiviral signaling (MAVS) adaptor in HHV-8 infection, we discovered that vFLIP expression was post-translationally up-regulated by the MAVS signaling complex on peroxisomes.Furthermore, we demonstrated that vFLIP could be targeted to the peroxisomes, where it was oncogenically active, in a PEX19-dependent manner.Targeted disruption of vFLIP and MAVS interaction resulted in a decrease in vFLIP expression and selectively promoted death of latently HHV-8-infected cells, providing therapeutic potential for treating HHV-8 diseases.Collectively, our experimental results suggest novel involvement of peroxisomes and MAVS in the stabilization of vFLIP and thereby in the establishment or maintenance of HHV-8 latency and associated pathogenesis. Author summaryHHV-8, also known as Kaposi's sarcoma associated herpesvirus (KSHV), is the etiological agent of several malignancies occurring in individuals with severe immunosuppression, as occurs in acquired immunodeficiency syndrome and transplantation.The viral latent proteins, required for persistent infection, are believed to contribute to pathogenesis.Amongst them, vFLIP has an oncogenic potential through activation of NF-κB and suppression of cell death induced by apoptosis and autophagy.Despite its functional significance, how the stability of the protein is regulated remains elusive.Here, we found that vFLIP can localize to peroxisomes where it is stabilized by its association with the mitochondria antiviral signaling adaptor protein MAVS, which mediates K63-linked polyubiquitination of vFLIP by TNF receptor-associated factors (TRAFs) and renders it resistant to degradation induced by autophagy and the ubiquitin-proteasome pathway.In addition, our genetic studies using MAVS-deficient HHV-8-infected cells revealed that MAVS is
Source: PLoS Pathogens
Authors: Young Bong Choi, Yeeun Choi, Edward William Harhaj
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,043
OpenAlex ID: W2801587813