HIV Nef enhances Tat-mediated viral transcription through a hnRNP-K-nucleated signaling complex.
Although dispensable in vitro, HIV Nef enables high-level viral replication in infected hosts by an as yet unexplained mechanism. Previously, we proposed that Nef functionally cooperates with the viral transactivator Tat by derepressing the viral promoter via a Nef-associated kinase complex (NAKC). Here, we demonstrate that hnRNP-K, a host factor thought to facilitate crosstalk between kinases and gene expression, interacts with Nef and, as part of NAKC, nucleates Nef-interacting kinases, including Lck, PKCdelta, and PI-3 kinase, leading to Lck and Erk1/2 activation. This strongly increased HIV transcription, which depended on Tat and the NF-kB motif in the viral promoter, but not on NF-kB activation. Depletion of hnRNP-K in a Jurkat model of HIV latency increased Erk1/2 activity and greatly augmented HIV reactivating stimuli. We conclude that hnRNP-K coordinates membrane signaling with transcriptional derepression through Erk1/2 and is targeted by HIV to enable Tat-mediated transcription.
Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Dietlinde
D
Wolf
Vanessa
V
Witte
Pat
P
Clark
Katja
K
Blume
Mathias G
MG
Lichtenheld
Andreas S
AS
Baur
D015967:Gene Expression Regulation, Viral; D006678:HIV / Q000502:physiology*; D034641:Heterogeneous-Nuclear Ribonucleoprotein K / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D025941:Protein Interaction Mapping; D051745:Protein Kinase C-delta / Q000378:metabolism; D012367:RNA, Viral / Q000096:biosynthesis*; D014158:Transcription, Genetic; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D012367:RNA, Viral; D054311:nef Gene Products, Human Immunodeficiency Virus; D054322:tat Gene Products, Human Immunodeficiency Virus; D019869:Phosphatidylinositol 3-Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051745:Protein Kinase C-delta; D048052:Mitogen-Activated Protein Kinase 3