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

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dc.creatorPyeon, Dohun
dc.creatorRojas, Vivian K.
dc.creatorPrice, Lenore
dc.creatorKim, Seongcheol
dc.creatorSingh, Meharvan
dc.creatorPark, In-Woo
dc.date.accessioned2022-11-15T22:34:38Z
dc.date.available2022-11-15T22:34:38Z
dc.date.issued2019-11-27
dc.description.abstractMolecular 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.
dc.description.sponsorshipThis work was funded by the NIH/NIDDK R01 DK099055 (I.-W. P).
dc.identifier.citationPyeon, D., Rojas, V. K., Price, L., Kim, S., Meharvan, S., & Park, I. W. (2019). HIV-1 Impairment via UBE3A and HIV-1 Nef Interactions Utilizing the Ubiquitin Proteasome System. Viruses, 11(12), 1098. https://doi.org/10.3390/v11121098
dc.identifier.issn1999-4915
dc.identifier.issue12
dc.identifier.urihttps://hdl.handle.net/20.500.12503/31923
dc.identifier.volume11
dc.publisherMDPI
dc.relation.urihttps://doi.org/10.3390/v11121098
dc.rights.holder© 2019 by the authors.
dc.rights.licenseAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceViruses
dc.subjectmetabolism
dc.subjectHIV-1 Nef
dc.subjectube3a (e6ap)
dc.subjectproteasomal degradation
dc.subjectubiquitin
dc.subjectubiquitin proteasome system
dc.subject.meshHIV Infections / virology
dc.subject.meshHIV-1 / physiology
dc.subject.meshHumans
dc.subject.meshProteasome Endopeptidase Complex
dc.subject.meshProteolysis
dc.subject.meshUbiquitin / metabolism
dc.subject.meshUbiquitin-Protein Ligases / genetics
dc.subject.meshUbiquitin-Protein Ligases / metabolism
dc.subject.meshUbiquitination
dc.subject.meshnef Gene Products, Human Immunodeficiency Virus / genetics
dc.subject.meshnef Gene Products, Human Immunodeficiency Virus / metabolism
dc.titleHIV-1 Impairment via UBE3A and HIV-1 Nef Interactions Utilizing the Ubiquitin Proteasome System
dc.typeArticle
dc.type.materialtext

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