The HIV-1 Nucleocapsid Regulates Its Own Condensation by Phase-Separated Activity-Enhancing Sequestration of the Viral Protease during Maturation

Autor: Xiao Tan, Robert J. Gorelick, Tuixent Escribà, Gilles Mirambeau, Carine Tisné, Mohamed Ouizougun-Oubari, Jean-Christophe Paillart, Sara Nieto-Marquez, Sébastien Lyonnais, Roland Marquet, Cristina Lorca-Oró, Michèle Reboud-Ravaux, S. Kashif Sadiq, Natalia Gabrielli, Andreas Meyerhans, José M. Gatell, Laure Dufau, Josephine Okoronkwo
Přispěvatelé: Centre d’études des Maladies Infectieuses et Pharmacologie Anti-Infectieuse - [Montpellier] (CEMIPAI), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Universitat Pompeu Fabra [Barcelona] (UPF), Heidelberg Institute for Theoretical Studies (HITS ), European Molecular Biology Laboratory (EMBL), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institució Catalana de Recerca i Estudis Avançats (ICREA), Expression Génétique Microbienne (EGM (UMR_8261 / FRE_3630)), Institut de biologie physico-chimique (IBPC (FR_550)), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Biologie intégrative des organismes marins (BIOM), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Observatoire océanologique de Banyuls (OOB), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), HAL-SU, Gestionnaire
Rok vydání: 2021
Předmět:
Zdroj: Viruses
Volume 13
Issue 11
Viruses, MDPI, 2021, 13 (11), pp.2312. ⟨10.3390/v13112312⟩
Viruses, 2021, 13 (11), pp.2312. ⟨10.3390/v13112312⟩
Viruses, Vol 13, Iss 2312, p 2312 (2021)
ISSN: 1999-4915
DOI: 10.3390/v13112312⟩
Popis: A growing number of studies indicate that mRNAs and long ncRNAs can affect protein populations by assembling dynamic ribonucleoprotein (RNP) granules. These phase-separated molecular 'sponges', stabilized by quinary (transient and weak) interactions, control proteins involved in numerous biological functions. Retroviruses such as HIV-1 form by self-assembly when their genomic RNA (gRNA) traps Gag and GagPol polyprotein precursors. Infectivity requires extracellular budding of the particle followed by maturation, an ordered processing of ∼2400 Gag and ∼120 GagPol by the viral protease (PR). This leads to a condensed gRNA-NCp7 nucleocapsid and a CAp24-self-assembled capsid surrounding the RNP. The choreography by which all of these components dynamically interact during virus maturation is one of the missing milestones to fully depict the HIV life cycle. Here, we describe how HIV-1 has evolved a dynamic RNP granule with successive weak-strong-moderate quinary NC-gRNA networks during the sequential processing of the GagNC domain. We also reveal two palindromic RNA-binding triads on NC, KxxFxxQ and QxxFxxK, that provide quinary NC-gRNA interactions. Consequently, the nucleocapsid complex appears properly aggregated for capsid reassembly and reverse transcription, mandatory processes for viral infectivity. We show that PR is sequestered within this RNP and drives its maturation/condensation within minutes, this process being most effective at the end of budding. We anticipate such findings will stimulate further investigations of quinary interactions and emergent mechanisms in crowded environments throughout the wide and growing array of RNP granules. This work was supported in part by the European Project THINPAD “Targeting the HIV-1 Nucleocapsid Protein to fight Antiretroviral Drug Resistance” (FP7-Grant Agreement 601969), by Foundation Clinic, by ANRS, by SIDACTION, and with federal funds from the NCI/NIH, under Contract No. HHSN261200800001E with Leidos Biomedical Research, Inc. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government (R.J.G.). S.L. acknowledges funding by the Marie-Curie IEF fellowship (FP7-Grant Agreement 237738) and is grateful to Maria Solà (IBMB-CSIC). S.K.S. and A.M. acknowledge support from amfAR Mathilde Krim Fellowship in Basic Biomedical Research number 108680 and the Spanish Ministry of Economy and Competitiveness and FEDER (Grant no. SAF2013-46077-R). S.K.S. also gratefully acknowledges support from the Volkswagen Foundation “Experiment! Funding Initiative” grant number 93874 and from the Klaus Tschira Stiftung.
Databáze: OpenAIRE
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