HIV-1 impairment via UBE3A and HIV-1 Nef interactions utilizing the ubiquitin proteasome system

Date

2021

Authors

Park, Inwoo

ORCID

Journal Title

Journal ISSN

Volume Title

Publisher

Abstract

HIV-1 life cycle regulation has thus far focused on viral gene stage-specificity, despite the quintessence of post-function protein elimination processes in the virus life cycle and consequent pathogenesis. Our studies demonstrated that a key pathogenic HIV-1 Nef interacted with ubiquitin-protein ligase E3A (UBE3A/E6AP), suggesting that interaction is integral to regulation of viral and cellular protein decay and thereby the competing HIV-1 and host cell survivals. In fact, Nef and UBE3A degraded reciprocally, and UBE3A-mediated degradation of Nef was significantly more potent than Nef-triggered degradation of UBE3A. Further, UBE3A degraded not only Nef but also HIV-1 structural proteins, Gag, thus significantly inhibiting HIV-1 replication in Jurkat T cells only in the presence of Nef, indicating that interaction between Nef and UBE3Awas pivotal for UBE3A-mediated degradation of the viral proteins. Nef and UBE3A were specific and antagonistic to each other in regulating proteasome activity and ubiquitination of cellular proteins in general, wherein specific domains of Nef overlapping with the long terminal repeat were essential for the observed actions. Further, Nef itself reduced the level of intracellular Gag by degrading a transcription regulator, Tat, demonstrating a broad role for Nef in the regulation of the HIV-1 life cycle. These data demonstrated that the Nef and UBE3A complex plays a crucial role in coordinating viral protein degradation and hence HIV-1 replication, providing insights into the nature of pathobiologic and defense strategies of HIV-1 and HIV-infected hosts.

Description

Keywords

Citation

Collections