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Two functional variants of AP-1 complex composed of either ³2 or ³1-subunits are independently required for MHC-I downregulation by HIV-1 Nef

Abstract

The HIV-1 accessory protein Nef downregulates cell surface expression of MHC-I molecules to facilitate virus spreading. The Nef-induced downregulation of MHC-I molecules, such as HLA-A, requires the clathrin adaptor protein 1 (AP-1) complex. The cooperative interaction of Nef, AP-1, and the cytosolic tail (CT) of HLA-A leads to redirection of HLA-A targeting from the trans-Golgi network (TGN) to lysosomes for degradation. Although the ³-adaptin subunit of AP-1 has two distinct isoforms (³1 and ³2), which may form two AP-1 complex variants, so far only the importance of AP-1³1 in MHC-I downregulation by Nef has been investigated. Here we report that the AP-1³2 isoform also participates in this process. We found that AP-1³2 forms a complex with Nef and HLA-A2_CT, and that this interaction depends on Y320 residue in HLA-A2_CT and Nef expression. Moreover, Nef targets AP-1³1 and AP-1³2 to different compartments in T cells, and depletion of either AP-1 variant impairs the Nef-mediated reduction of endogenous HLA-A total levels, and rescues HLA-A levels in the cell surface. Finally, immunofluorescence and immuno-electron microscopy analyses reveal that the depletion of ³2 in T cells compromises both Nef-mediated retention of HLA-A molecules in the TGN, and targeting to multivesicular bodies/late endosomes. Altogether, these results show that in addition to AP-1³1, Nef also requires the AP-1³2 variant for efficient MHC-I downregulation. (AU)

Articles published in Agência FAPESP Newsletter about the research grant:
Podrían surgir nuevos medicamentos anti-VIH gracias al hallazgo del ‘talón de Aquiles’ de una proteína 
Discovery of protein’s ‘Achilles heel’ paves way for novel class of anti-HIV drugs 
Descoberta de ‘calcanhar de aquiles’ de proteína abre caminho para nova classe de medicamentos anti-HIV 
Articles published in other media outlets (27 total):
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Folha de S. Paulo: Descoberta pode gerar novas drogas anti-HIV (19/Sep/2020)
Folha.com: Conhecimento sobre estrutura de proteína abre caminho para novas drogas anti-HIV (18/Sep/2020)
UOL: Descoberta de proteína abre porta para nova classe de medicamentos anti-HIV (15/Sep/2020)
Agência de Notícias da Aids: RETROSPECTIVA 2020: Descoberta de proteína abre porta para nova classe de medicamentos anti-HIV (05/Jan/2021)
Al Día (Cuba): El hallazgo del ‘talón de Aquiles’ de una proteína abre la puerta a nuevos medicamentos anti-VIH (01/Dec/2020)
News Medical (Austrália): Discovery of protein crucial to HIV virulence could lead to new class of drugs (17/Nov/2020)
Medical Xpress (Reino Unido): Discovery of protein's 'Achilles heel' paves way for novel class of anti-HIV drugs (17/Nov/2020)
Health Medicine Network (EUA): Discovery of protein’s ‘Achilles heel’ paves way for novel class of anti-HIV drugs (17/Nov/2020)
Agenparl (Itália): Discovery of protein's 'Achilles heel' paves way for novel class of anti-HIV drugs (17/Nov/2020)
Health News: Discovery of protein’s ‘Achilles heel’ paves way for novel class of anti-HIV drugs (17/Nov/2020)
KingfirthHealthandFitness: Discovery of protein's 'Achilles heel' paves way for novel class of anti-HIV drugs (17/Nov/2020)
AZo Life Sciences: Discovery of 'Achilles heel' in protein crucial to HIV virulence paves way for new drugs (17/Nov/2020)
Polymerelektronik.org: Discovery of protein’s ‘Achilles heel’ paves way for novel class of anti-HIV drugs (17/Nov/2020)
The Uncover Reality (Índia): Discovery of Protein’s ‘Achilles Heel’ Paves Way for Novel Class of Anti-HIV Drugs (Biology) (17/Nov/2020)
Science Codex: Discovery of protein's 'Achilles heel' paves way for novel class of anti-HIV drugs (16/Nov/2020)
Scientific Inquirer (EUA): Discovery holds potential for new class of HIV drugs (16/Nov/2020)
Scienmag Science Magazine (Reino Unido): Discovery Of Protein’s ‘Achilles Heel’ Paves Way For Novel Class Of Anti-HIV Drugs (16/Nov/2020)
Brightsurf: Discovery of protein's 'Achilles heel' paves way for novel class of anti-HIV drugs (16/Nov/2020)
Arabicpost.net: The discovery of the “Achilles heel” protein paves the way for a new class of anti-HIV drugs (16/Nov/2020)
Biblioteca FMUSP: Descoberta de “calcanhar de aquiles” da proteína Nef, crucial na virulência do HIV e em sua capacidade de desencadear a Aids (25/Sep/2020)
Revide: USP de Ribeirão Preto faz descoberta importante no combate ao HIV (20/Sep/2020)
SP Agora: Descoberta de cientistas brasileiros pode levar a remédios mais eficientes contra HIV (18/Sep/2020)
Agência de Notícias da Aids: Descoberta de proteína abre porta para nova classe de medicamentos anti-HIV (17/Sep/2020)
LabNetwork: Descoberta de ‘calcanhar de aquiles’ de proteína abre caminho para nova classe de medicamentos anti-HIV (16/Sep/2020)
Portal Thathi: Pesquisa da USP de Ribeirão descobre ‘calcanhar de aquiles’ do vírus HIV e abre caminho para novo medicamento (15/Sep/2020)
Jornal Integração: Descoberta de proteína abre caminho para nova classe de medicamentos anti-HIV (15/Sep/2020)
Coluna Supinando: Descoberta abre caminho para nova classe de medicamentos anti-HIV (15/Sep/2020)