The CREB Regulated Transcription Coactivator 2 Suppresses HIV-1 Transcription by Preventing RNA Pol II from Binding to HIV-1 LTR

Ling Ma; Shumin Chen; Zhen Wang; Saisai Guo; Jianyuan Zhao; Dongrong Yi; Quanjie Li; Zhenlong Liu; Fei Guo; Xiaoyu Li; Pingping Jia; Jiwei Ding; Chen Liang; Shan Cen

doi:10.1007/s12250-021-00363-1

The CREB Regulated Transcription Coactivator 2 Suppresses HIV-1 Transcription by Preventing RNA Pol II from Binding to HIV-1 LTR

Virol Sin. 2021 Aug;36(4):796-809. doi: 10.1007/s12250-021-00363-1. Epub 2021 Mar 15.

Authors

Ling Ma^#¹, Shumin Chen^#², Zhen Wang^#³, Saisai Guo¹, Jianyuan Zhao¹, Dongrong Yi¹, Quanjie Li¹, Zhenlong Liu³, Fei Guo⁴, Xiaoyu Li¹, Pingping Jia⁵, Jiwei Ding^{6

7}, Chen Liang³, Shan Cen^{8

9

10}

Affiliations

¹ Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing, 100050, China.
² Department of Blood Transfusion, The Affiliated Hospital of Qingdao University, Qingdao 266000, China.
³ Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, H3T 1E2, Canada.
⁴ Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing, 100176, China.
⁵ Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China.
⁶ Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing, 100050, China. dingjiwei@imb.pumc.edu.cn.
⁷ CAMS Key Laboratory of Antiviral Drug Research, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100050, China. dingjiwei@imb.pumc.edu.cn.
⁸ Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing, 100050, China. shancen@imb.pumc.edu.cn.
⁹ CAMS Key Laboratory of Antiviral Drug Research, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100050, China. shancen@imb.pumc.edu.cn.
¹⁰ Beijing Friendship Hospital, Capital Medical University, Beijing, 100029, China. shancen@imb.pumc.edu.cn.

^# Contributed equally.

Abstract

The CREB-regulated transcriptional co-activators (CRTCs), including CRTC1, CRTC2 and CRTC3, enhance transcription of CREB-targeted genes. In addition to regulating host gene expression in response to cAMP, CRTCs also increase the infection of several viruses. While human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) promoter harbors a cAMP response element and activation of the cAMP pathway promotes HIV-1 transcription, it remains unknown whether CRTCs have any effect on HIV-1 transcription and HIV-1 infection. Here, we reported that CRTC2 expression was induced by HIV-1 infection, but CRTC2 suppressed HIV-1 infection and diminished viral RNA expression. Mechanistic studies revealed that CRTC2 inhibited transcription from HIV-1 LTR and diminished RNA Pol II occupancy at the LTR independent of its association with CREB. Importantly, CRTC2 inhibits the activation of latent HIV-1. Together, these data suggest that in response to HIV-1 infection, cells increase the expression of CRTC2 which inhibits HIV-1 gene expression and may play a role in driving HIV-1 into latency.

Keywords: CREB regulated transcription coactivator 2 (CRTC2); Human immunodeficiency virus (HIV); Infection; Latency; Long terminal repeat (LTR); RNA polymerase II (RNA Pol II); Viral transcription; Virology.

MeSH terms

HIV Infections*
HIV Long Terminal Repeat / genetics
HIV-1* / genetics
HIV-1* / metabolism
Humans
RNA Polymerase II / genetics
RNA Polymerase II / metabolism
Transcription Factors* / genetics
Virus Latency

Substances

CRTC1 protein, human
CRTC2 protein, human
CRTC3 protein, human
Transcription Factors
RNA Polymerase II