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Open AccessArticle

HIV-1 Impairment via UBE3A and HIV-1 Nef Interactions Utilizing the Ubiquitin Proteasome System

1
Departments of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA
2
Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
3
Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
*
Author to whom correspondence should be addressed.
Current address: Department of Cellular and Molecular Physiology, Loyola University Chicago, Stritch School of Medicine, Maywood, IL 60153, USA.
Viruses 2019, 11(12), 1098; https://doi.org/10.3390/v11121098
Received: 21 September 2019 / Revised: 15 November 2019 / Accepted: 25 November 2019 / Published: 27 November 2019
(This article belongs to the Section Animal Viruses)
Molecular basis of 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 viral protein, Nef, interacted with ubiquitin (Ub)-protein ligase E3A (UBE3A/E6AP), suggesting that interaction between Nef and UBE3A 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. Mechanistic study showed that 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 (LTR) were essential for the observed actions. Further, Nef itself reduced the level of intracellular Gag by degrading a cardinal transcription regulator, Tat, demonstrating a broad role for Nef in the regulation of the HIV-1 life cycle. Taken together, 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 as to the nature of pathobiologic and defense strategies of HIV-1 and HIV-infected host cells. View Full-Text
Keywords: HIV-1 Nef; UBE3A (E6AP); ubiquitin; ubiquitin proteasome system; proteasomal degradation HIV-1 Nef; UBE3A (E6AP); ubiquitin; ubiquitin proteasome system; proteasomal degradation
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Pyeon, D.; Rojas, V.K.; Price, L.; Kim, S.; Singh, M.; Park, I.-W. HIV-1 Impairment via UBE3A and HIV-1 Nef Interactions Utilizing the Ubiquitin Proteasome System. Viruses 2019, 11, 1098.

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