HIV-1 Tat Recruits HDM2 E3 Ligase To Target IRF-1 for Ubiquitination and Proteasomal Degradation

ABSTRACT In addition to its ability to regulate HIV-1 promoter activation, the viral transactivator Tat also functions as a determinant of pathogenesis and disease progression by directly and indirectly modulating the host anti-HIV response, largely through the capacity of Tat to interact with and m...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Anna Lisa Remoli, Giulia Marsili, Edvige Perrotti, Chiara Acchioni, Marco Sgarbanti, Alessandra Borsetti, John Hiscott, Angela Battistini
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/9efa615d83b048c78b202507715f46d3
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:9efa615d83b048c78b202507715f46d3
record_format	dspace
spelling	oai:doaj.org-article:9efa615d83b048c78b202507715f46d32021-11-15T15:50:14ZHIV-1 Tat Recruits HDM2 E3 Ligase To Target IRF-1 for Ubiquitination and Proteasomal Degradation10.1128/mBio.01528-162150-7511https://doaj.org/article/9efa615d83b048c78b202507715f46d32016-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01528-16https://doaj.org/toc/2150-7511ABSTRACT In addition to its ability to regulate HIV-1 promoter activation, the viral transactivator Tat also functions as a determinant of pathogenesis and disease progression by directly and indirectly modulating the host anti-HIV response, largely through the capacity of Tat to interact with and modulate the activities of multiple host proteins. We previously demonstrated that Tat modulated both viral and host transcriptional machinery by interacting with the cellular transcription factor interferon regulatory factor 1 (IRF-1). In the present study, we investigated the mechanistic basis and functional significance of Tat−IRF-1 interaction and demonstrate that Tat dramatically decreased IRF-1 protein stability. To accomplish this, Tat exploited the cellular HDM2 (human double minute 2 protein) ubiquitin ligase to accelerate IRF-1 proteasome-mediated degradation, resulting in a quenching of IRF-1 transcriptional activity during HIV-1 infection. These data identify IRF-1 as a new target of Tat-induced modulation of the cellular protein machinery and reveal a new strategy developed by HIV-1 to evade host immune responses. IMPORTANCE Current therapies have dramatically reduced morbidity and mortality associated with HIV infection and have converted infection from a fatal pathology to a chronic disease that is manageable via antiretroviral therapy. Nevertheless, HIV-1 infection remains a challenge, and the identification of useful cellular targets for therapeutic intervention remains a major goal. The cellular transcription factor IRF-1 impacts various physiological functions, including the immune response to viral infection. In this study, we have identified a unique mechanism by which HIV-1 evades IRF-1-mediated host immune responses and show that the viral protein Tat accelerates IRF-1 proteasome-mediated degradation and inactivates IRF-1 function. Restoration of IRF-1 functionality may thus be regarded as a potential strategy to reinstate both a direct antiviral response and a more broadly acting immune regulatory circuit.Anna Lisa RemoliGiulia MarsiliEdvige PerrottiChiara AcchioniMarco SgarbantiAlessandra BorsettiJohn HiscottAngela BattistiniAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 5 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Anna Lisa Remoli Giulia Marsili Edvige Perrotti Chiara Acchioni Marco Sgarbanti Alessandra Borsetti John Hiscott Angela Battistini HIV-1 Tat Recruits HDM2 E3 Ligase To Target IRF-1 for Ubiquitination and Proteasomal Degradation
description	ABSTRACT In addition to its ability to regulate HIV-1 promoter activation, the viral transactivator Tat also functions as a determinant of pathogenesis and disease progression by directly and indirectly modulating the host anti-HIV response, largely through the capacity of Tat to interact with and modulate the activities of multiple host proteins. We previously demonstrated that Tat modulated both viral and host transcriptional machinery by interacting with the cellular transcription factor interferon regulatory factor 1 (IRF-1). In the present study, we investigated the mechanistic basis and functional significance of Tat−IRF-1 interaction and demonstrate that Tat dramatically decreased IRF-1 protein stability. To accomplish this, Tat exploited the cellular HDM2 (human double minute 2 protein) ubiquitin ligase to accelerate IRF-1 proteasome-mediated degradation, resulting in a quenching of IRF-1 transcriptional activity during HIV-1 infection. These data identify IRF-1 as a new target of Tat-induced modulation of the cellular protein machinery and reveal a new strategy developed by HIV-1 to evade host immune responses. IMPORTANCE Current therapies have dramatically reduced morbidity and mortality associated with HIV infection and have converted infection from a fatal pathology to a chronic disease that is manageable via antiretroviral therapy. Nevertheless, HIV-1 infection remains a challenge, and the identification of useful cellular targets for therapeutic intervention remains a major goal. The cellular transcription factor IRF-1 impacts various physiological functions, including the immune response to viral infection. In this study, we have identified a unique mechanism by which HIV-1 evades IRF-1-mediated host immune responses and show that the viral protein Tat accelerates IRF-1 proteasome-mediated degradation and inactivates IRF-1 function. Restoration of IRF-1 functionality may thus be regarded as a potential strategy to reinstate both a direct antiviral response and a more broadly acting immune regulatory circuit.
format	article
author	Anna Lisa Remoli Giulia Marsili Edvige Perrotti Chiara Acchioni Marco Sgarbanti Alessandra Borsetti John Hiscott Angela Battistini
author_facet	Anna Lisa Remoli Giulia Marsili Edvige Perrotti Chiara Acchioni Marco Sgarbanti Alessandra Borsetti John Hiscott Angela Battistini
author_sort	Anna Lisa Remoli
title	HIV-1 Tat Recruits HDM2 E3 Ligase To Target IRF-1 for Ubiquitination and Proteasomal Degradation
title_short	HIV-1 Tat Recruits HDM2 E3 Ligase To Target IRF-1 for Ubiquitination and Proteasomal Degradation
title_full	HIV-1 Tat Recruits HDM2 E3 Ligase To Target IRF-1 for Ubiquitination and Proteasomal Degradation
title_fullStr	HIV-1 Tat Recruits HDM2 E3 Ligase To Target IRF-1 for Ubiquitination and Proteasomal Degradation
title_full_unstemmed	HIV-1 Tat Recruits HDM2 E3 Ligase To Target IRF-1 for Ubiquitination and Proteasomal Degradation
title_sort	hiv-1 tat recruits hdm2 e3 ligase to target irf-1 for ubiquitination and proteasomal degradation
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/9efa615d83b048c78b202507715f46d3
work_keys_str_mv	AT annalisaremoli hiv1tatrecruitshdm2e3ligasetotargetirf1forubiquitinationandproteasomaldegradation AT giuliamarsili hiv1tatrecruitshdm2e3ligasetotargetirf1forubiquitinationandproteasomaldegradation AT edvigeperrotti hiv1tatrecruitshdm2e3ligasetotargetirf1forubiquitinationandproteasomaldegradation AT chiaraacchioni hiv1tatrecruitshdm2e3ligasetotargetirf1forubiquitinationandproteasomaldegradation AT marcosgarbanti hiv1tatrecruitshdm2e3ligasetotargetirf1forubiquitinationandproteasomaldegradation AT alessandraborsetti hiv1tatrecruitshdm2e3ligasetotargetirf1forubiquitinationandproteasomaldegradation AT johnhiscott hiv1tatrecruitshdm2e3ligasetotargetirf1forubiquitinationandproteasomaldegradation AT angelabattistini hiv1tatrecruitshdm2e3ligasetotargetirf1forubiquitinationandproteasomaldegradation
_version_	1718427475425361920

HIV-1 Tat Recruits HDM2 E3 Ligase To Target IRF-1 for Ubiquitination and Proteasomal Degradation

Ejemplares similares