ISG15 Deficiency Enhances HIV-1 Infection by Accumulating Misfolded p53

ABSTRACT Macrophages and dendritic cells dominate early immune responses to lentiviruses. HIV-1 sensing by pathogen recognition receptors induces signaling cascades that culminate in type I alpha/beta interferon (IFN-α/β) induction. IFN-α/β signals back via the IFN-α/β receptors, inducing a plethora...

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Autores principales:	Edmund Osei Kuffour, Renate König, Dieter Häussinger, Wolfgang A. Schulz, Carsten Münk
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	HIV-1 THP-1 USP18 p21 p53 Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c3924f0025a64596b5afd0d46b6f4860
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spelling	oai:doaj.org-article:c3924f0025a64596b5afd0d46b6f48602021-11-15T16:22:08ZISG15 Deficiency Enhances HIV-1 Infection by Accumulating Misfolded p5310.1128/mBio.01342-192150-7511https://doaj.org/article/c3924f0025a64596b5afd0d46b6f48602019-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01342-19https://doaj.org/toc/2150-7511ABSTRACT Macrophages and dendritic cells dominate early immune responses to lentiviruses. HIV-1 sensing by pathogen recognition receptors induces signaling cascades that culminate in type I alpha/beta interferon (IFN-α/β) induction. IFN-α/β signals back via the IFN-α/β receptors, inducing a plethora of IFN-stimulated gene (ISGs), including ISG15, p53, and p21Cip1. p21 inhibits HIV-1 replication by inactivating the deoxynucleoside triphosphate (dNTP) biosynthesis pathway and activating the restriction factor SAMHD1. p21 is induced by functional p53. ISG15-specific isopeptidase USP18 negatively regulates IFN signaling. We showed previously that USP18 contributes to HIV-1 replication by abrogating p21 antiviral function. Here, we demonstrate a mechanism by which USP18 mediates p21 downregulation in myeloid cells. USP18, by its protease activity, accumulates misfolded p53, which requires ISG15 for its degradation. Depletion of ISG15 causes accumulation of misfolded dominant negative p53, which enhances HIV-1 replication. This work clarifies the function and consequences of p53 modification by ISG15 and implicates USP18 in HIV-1 infection and potentially in carcinogenesis. IMPORTANCE HIV-1 has evolved many strategies to circumvent the host’s antiviral innate immune responses and establishes disseminated infection; the molecular mechanisms of these strategies are not entirely clear. We showed previously that USP18 contributes to HIV-1 replication by abrogating p21 antiviral function. Here, we demonstrate a mechanism by which USP18 mediates p21 downregulation in myeloid cells. USP18, by its protease activity, accumulates misfolded p53, which requires ISG15 for clearance. Depletion of ISG15 causes accumulation of misfolded dominant negative p53, which supports HIV-1 replication. This work clarifies the function and consequences of p53 modification by ISG15 and implicates USP18 in HIV-1 infection and potentially in carcinogenesis.Edmund Osei KuffourRenate KönigDieter HäussingerWolfgang A. SchulzCarsten MünkAmerican Society for MicrobiologyarticleHIV-1THP-1USP18p21p53MicrobiologyQR1-502ENmBio, Vol 10, Iss 4 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	HIV-1 THP-1 USP18 p21 p53 Microbiology QR1-502
spellingShingle	HIV-1 THP-1 USP18 p21 p53 Microbiology QR1-502 Edmund Osei Kuffour Renate König Dieter Häussinger Wolfgang A. Schulz Carsten Münk ISG15 Deficiency Enhances HIV-1 Infection by Accumulating Misfolded p53
description	ABSTRACT Macrophages and dendritic cells dominate early immune responses to lentiviruses. HIV-1 sensing by pathogen recognition receptors induces signaling cascades that culminate in type I alpha/beta interferon (IFN-α/β) induction. IFN-α/β signals back via the IFN-α/β receptors, inducing a plethora of IFN-stimulated gene (ISGs), including ISG15, p53, and p21Cip1. p21 inhibits HIV-1 replication by inactivating the deoxynucleoside triphosphate (dNTP) biosynthesis pathway and activating the restriction factor SAMHD1. p21 is induced by functional p53. ISG15-specific isopeptidase USP18 negatively regulates IFN signaling. We showed previously that USP18 contributes to HIV-1 replication by abrogating p21 antiviral function. Here, we demonstrate a mechanism by which USP18 mediates p21 downregulation in myeloid cells. USP18, by its protease activity, accumulates misfolded p53, which requires ISG15 for its degradation. Depletion of ISG15 causes accumulation of misfolded dominant negative p53, which enhances HIV-1 replication. This work clarifies the function and consequences of p53 modification by ISG15 and implicates USP18 in HIV-1 infection and potentially in carcinogenesis. IMPORTANCE HIV-1 has evolved many strategies to circumvent the host’s antiviral innate immune responses and establishes disseminated infection; the molecular mechanisms of these strategies are not entirely clear. We showed previously that USP18 contributes to HIV-1 replication by abrogating p21 antiviral function. Here, we demonstrate a mechanism by which USP18 mediates p21 downregulation in myeloid cells. USP18, by its protease activity, accumulates misfolded p53, which requires ISG15 for clearance. Depletion of ISG15 causes accumulation of misfolded dominant negative p53, which supports HIV-1 replication. This work clarifies the function and consequences of p53 modification by ISG15 and implicates USP18 in HIV-1 infection and potentially in carcinogenesis.
format	article
author	Edmund Osei Kuffour Renate König Dieter Häussinger Wolfgang A. Schulz Carsten Münk
author_facet	Edmund Osei Kuffour Renate König Dieter Häussinger Wolfgang A. Schulz Carsten Münk
author_sort	Edmund Osei Kuffour
title	ISG15 Deficiency Enhances HIV-1 Infection by Accumulating Misfolded p53
title_short	ISG15 Deficiency Enhances HIV-1 Infection by Accumulating Misfolded p53
title_full	ISG15 Deficiency Enhances HIV-1 Infection by Accumulating Misfolded p53
title_fullStr	ISG15 Deficiency Enhances HIV-1 Infection by Accumulating Misfolded p53
title_full_unstemmed	ISG15 Deficiency Enhances HIV-1 Infection by Accumulating Misfolded p53
title_sort	isg15 deficiency enhances hiv-1 infection by accumulating misfolded p53
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/c3924f0025a64596b5afd0d46b6f4860
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ISG15 Deficiency Enhances HIV-1 Infection by Accumulating Misfolded p53

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