TY - JOUR
T1 - ADAP1 promotes latent HIV-1 reactivation by selectively tuning KRAS–ERK–AP-1 T cell signaling-transcriptional axis
AU - Ramirez, Nora Guadalupe P.
AU - Lee, Jeon
AU - Zheng, Yue
AU - Li, Lianbo
AU - Dennis, Bryce
AU - Chen, Didi
AU - Challa, Ashwini
AU - Planelles, Vicente
AU - Westover, Kenneth D.
AU - Alto, Neal M.
AU - D’Orso, Iván
N1 - Funding Information:
We fully appreciate the UTSW McDermott Center Sequencing Core for assistance in scRNAseq experiments and A. Lemoff at the UTSW Proteomics Core for assistance with proteomics experiments. The authors appreciate the assistance of the UTSW Live Cell Imaging Facility, a shared resource of the Harold C. Simmons Comprehensive Cancer Center, supported in part by an NCI Cancer Center Support Grant, 1P30 CA142543-01. We thank J. Schoggins and lab for the vector pTRIP.CMV.IVSB.IRES.TagRFP. We thank M. Mettlen for guidance on the cell fractionation protocol. We also thank the rest of the D’Orso lab for valuable feedback throughout the project. This research was supported in part by US National Institutes of Health (NIH) under award numbers R01AI114362 and R21AI155071 (to I.D). N.-G.P.R. was supported by NIH Pharmacological Sciences Training grant GM007062 and a 2016 pre-doctoral fellowship from the Ford Foundation. J.L. was supported by the Cancer Prevention Research Institute of Texas (CPRIT; RP150596). V.P. was supported by NIH grant AI143567-02. K.D.W. was supported by NIH R01CA244341-01 and the Cancer Prevention Research Institute of Texas (CPRIT) RP170373.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Immune stimulation fuels cell signaling-transcriptional programs inducing biological responses to eliminate virus-infected cells. Yet, retroviruses that integrate into host cell chromatin, such as HIV-1, co-opt these programs to switch between latent and reactivated states; however, the regulatory mechanisms are still unfolding. Here, we implemented a functional screen leveraging HIV-1’s dependence on CD4+ T cell signaling-transcriptional programs and discovered ADAP1 is an undescribed modulator of HIV-1 proviral fate. Specifically, we report ADAP1 (ArfGAP with dual PH domain-containing protein 1), a previously thought neuronal-restricted factor, is an amplifier of select T cell signaling programs. Using complementary biochemical and cellular assays, we demonstrate ADAP1 inducibly interacts with the immune signalosome to directly stimulate KRAS GTPase activity thereby augmenting T cell signaling through targeted activation of the ERK–AP-1 axis. Single cell transcriptomics analysis revealed loss of ADAP1 function blunts gene programs upon T cell stimulation consequently dampening latent HIV-1 reactivation. Our combined experimental approach defines ADAP1 as an unexpected tuner of T cell programs facilitating HIV-1 latency escape.
AB - Immune stimulation fuels cell signaling-transcriptional programs inducing biological responses to eliminate virus-infected cells. Yet, retroviruses that integrate into host cell chromatin, such as HIV-1, co-opt these programs to switch between latent and reactivated states; however, the regulatory mechanisms are still unfolding. Here, we implemented a functional screen leveraging HIV-1’s dependence on CD4+ T cell signaling-transcriptional programs and discovered ADAP1 is an undescribed modulator of HIV-1 proviral fate. Specifically, we report ADAP1 (ArfGAP with dual PH domain-containing protein 1), a previously thought neuronal-restricted factor, is an amplifier of select T cell signaling programs. Using complementary biochemical and cellular assays, we demonstrate ADAP1 inducibly interacts with the immune signalosome to directly stimulate KRAS GTPase activity thereby augmenting T cell signaling through targeted activation of the ERK–AP-1 axis. Single cell transcriptomics analysis revealed loss of ADAP1 function blunts gene programs upon T cell stimulation consequently dampening latent HIV-1 reactivation. Our combined experimental approach defines ADAP1 as an unexpected tuner of T cell programs facilitating HIV-1 latency escape.
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U2 - 10.1038/s41467-022-28772-0
DO - 10.1038/s41467-022-28772-0
M3 - Article
C2 - 35232997
AN - SCOPUS:85125589111
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1109
ER -