HIV-1 Nef assembles a Src family kinase-ZAP-70/Syk-PI3K cascade to downregulate cell-surface MHC-I.
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.
Hung
Chien-Hui
CH
Vollum Institute, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA.
Thomas
Laurel
L
Ruby
Carl E
CE
Atkins
Katelyn M
KM
Morris
Nicholas P
NP
Knight
Zachary A
ZA
Scholz
Isabel
I
Barklis
Eric
E
Weinberg
Andrew D
AD
Shokat
Kevan M
KM
Thomas
Gary
G
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*
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