The adaptor protein SLP-76 regulates HIV-1 release and cell-to-cell transmission in T cells.
HIV-1 infection in T cells is regulated by TCR activation. However, the cellular proteins of the TCR pathway that regulate HIV-1 infection are poorly characterized. In this study, in HIV-1 infection, we observed a significant reduction of HIV-1 virus production in Src homology 2 domain-containing leukocyte protein of 76 kDa (SLP-76)-deficient Jurkat T cells compared with wild-type and SLP-76-reconstituted Jurkat T cells. We further confirmed the role of SLP-76 in HIV-1 infection by small interfering RNA-mediated knockdown in MT4 cells and PBMCs. Structural-functional analysis revealed that the N-terminal domain of SLP-76 was important for regulating HIV-1 infection. Further mechanistic studies revealed that lack of SLP-76 impaired virus release, but did not affect viral entry, integration, and transcription. We also showed that SLP-76 plays a critical role in cell-to-cell transmission of HIV-1. Signaling studies revealed that SLP-76 associated with viral negative regulatory factor protein and multiple signaling molecules during HIV-1 infection. Furthermore, SLP-76 facilitated the association of negative regulatory factor and F-actin, suggesting that SLP-76 mediates the formation of a signaling complex that may regulate viral release via cytoskeletal changes. Taken together, our studies demonstrate a novel role for the adaptor molecule SLP-76 in regulating HIV-1 infection in T cells with the potential to develop innovative strategies against HIV-1.
Department of Pathology, Ohio State University Medical Center, Columbus, OH 43210, USA.
Tirumuru
T
Nagaraja
Appakkudal R
AR
Anand
Helong
H
Zhao
Ramesh K
RK
Ganju
D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology / Q000378:metabolism*; D015153:Blotting, Western; D002469:Cell Separation; D005434:Flow Cytometry; D015497:HIV-1 / Q000276:immunology / Q000378:metabolism* / Q000472:pathogenicity*; D006801:Humans; D019169:Jurkat Cells; D018613:Microscopy, Confocal; D010750:Phosphoproteins / Q000276:immunology / Q000378:metabolism*; D034741:RNA, Small Interfering; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology*; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D034741:RNA, Small Interfering; C092947:SLP-76 signal Transducing adaptor proteins