HIV-1 Nef assembles a Src family kinase-ZAP-70/Syk-PI3K cascade to downregulate cell-surface MHC-I.

Abstract:

:HIV-1 Nef, which is required for the efficient onset of AIDS, enhances viral replication and infectivity by exerting multiple effects on infected cells. Nef downregulates cell-surface MHC-I molecules by an uncharacterized PI3K pathway requiring the actions of two Nef motifs-EEEE(65) and PXXP(75). We report that the Nef EEEE(65) targeting motif enables Nef PXXP(75) to bind and activate a trans-Golgi network-localized Src family tyrosine kinase (SFK). The Nef/SFK complex then recruits and phosphorylates the tyrosine kinase ZAP-70, which binds class I PI3K to trigger MHC-I downregulation in primary CD4+ T cells. In promonocytic cells, Nef/SFK recruits the ZAP-70 homolog Syk to downregulate MHC-I, implicating this PI3K pathway in multiple HIV-1 reservoirs. Isoform-specific PI3K inhibitors repress MHC-I downregulation, identifying them as potential therapeutic agents to combat HIV-1. The discovery of this Nef-SFK-ZAP-70/Syk-PI3K signaling pathway explains the hierarchal role of the Nef motifs in effecting immunoevasion.

journal_name

Cell Host Microbe

journal_title

Cell host & microbe

authors

Hung CH,Thomas L,Ruby CE,Atkins KM,Morris NP,Knight ZA,Scholz I,Barklis E,Weinberg AD,Shokat KM,Thomas G

doi

10.1016/j.chom.2007.03.004

subject

Has Abstract

pub_date

2007-04-19 00:00:00

pages

121-33

issue

2

eissn

1931-3128

issn

1934-6069

pii

S1931-3128(07)00043-1

journal_volume

1

pub_type

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