title: 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.
authors.affiliation: Vollum Institute, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Chien-Hui
authors.initials: CH
authors.lastname: Hung
authors.forename: Laurel
authors.initials: L
authors.lastname: Thomas
authors.forename: Carl E
authors.initials: CE
authors.lastname: Ruby
authors.forename: Katelyn M
authors.initials: KM
authors.lastname: Atkins
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Morris
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Knight
authors.forename: Isabel
authors.initials: I
authors.lastname: Scholz
authors.forename: Eric
authors.initials: E
authors.lastname: Barklis
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Weinberg
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
authors.forename: Gary
authors.initials: G
authors.lastname: Thomas
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D002460:Cell Line; D002462:Cell Membrane / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D015497:HIV-1 / Q000502:physiology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D008285:Major Histocompatibility Complex; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering / Q000235:genetics; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism*; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000502:physiology*
chemical_list: D015395:Histocompatibility Antigens Class I; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; D051746:ZAP-70 Protein-Tyrosine Kinase; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1