Suppression of HIV-1 Nef translation by Sam68 mutant-induced stress granules and nef mRNA sequestration.
HIV-1 Nef plays important roles in HIV-1 replication and pathogenesis. It is translated from completely spliced HIV-1 RNA, and its expression is inherently regulated at the levels of viral DNA transcription and RNA splicing. Here we show that Sam68 cytoplasmic mutants potently suppress Nef expression. The suppression requires Sam68 domain aa 269-321 and is correlated with its ability to induce stress granules. In addition, the suppression is specific to Nef, and direct binding to nef mRNA 3'UTR confers the suppression specificity. Furthermore, nef mRNA is targeted to and enriched in these induced stress granules. Importantly, Nef suppression occurs in the context of HIV-1 infection of CD4+ T lymphocytes with little MHC I and CD4 downregulation. Taken together, these results demonstrate that stress granule induction and nef mRNA sequestration account for this translational suppression of Nef expression and offer a strategy for development of anti-HIV therapeutics to buttress our fight against HIV/AIDS.
Henao-Mejia
Jorge
J
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Liu
Ying
Y
Park
In-Woo
IW
Zhang
Jizhong
J
Sanford
Jeremy
J
He
Johnny J
JJ
D020413:3' Untranslated Regions / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D003594:Cytoplasmic Granules / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D015536:Down-Regulation; D015497:HIV-1 / Q000235:genetics* / Q000502:physiology; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D011485:Protein Binding; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D034443:RNA Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism; D013489:Suppression, Genetic; D013601:T-Lymphocytes / Q000166:cytology / Q000821:virology; D014779:Virus Replication; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics* / Q000378:metabolism*
D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D004268:DNA-Binding Proteins; D015395:Histocompatibility Antigens Class I; C489559:KHDRBS1 protein, human; D050505:Mutant Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus