Proteomic profiling of HIV-1 infection of human CD4+ T cells identifies PSGL-1 as an HIV restriction factor

Ying Liu; Yajing Fu; Qian Wang; Mushan Li; Zheng Zhou; Deemah Dabbagh; Chunyan Fu; Hang Zhang; Shuo Li; Tengjiang Zhang; Jing Gong; Xiaohui Kong; Weiwei Zhai; Jiaming Su; Jianping Sun; Yonghong Zhang; Xiao-Fang Yu; Zhen Shao; Feng Zhou; Yuntao Wu; Xu Tan

doi:10.1038/s41564-019-0372-2

Proteomic profiling of HIV-1 infection of human CD4⁺ T cells identifies PSGL-1 as an HIV restriction factor

Nat Microbiol. 2019 May;4(5):813-825. doi: 10.1038/s41564-019-0372-2. Epub 2019 Mar 4.

Authors

Ying Liu^#¹, Yajing Fu^#^{2

3}, Qian Wang⁴, Mushan Li⁵, Zheng Zhou³, Deemah Dabbagh³, Chunyan Fu¹, Hang Zhang¹, Shuo Li¹, Tengjiang Zhang¹, Jing Gong¹, Xiaohui Kong¹, Weiwei Zhai^{6

7}, Jiaming Su⁸, Jianping Sun⁹, Yonghong Zhang⁹, Xiao-Fang Yu⁸, Zhen Shao⁵, Feng Zhou¹⁰, Yuntao Wu¹¹, Xu Tan¹²

Affiliations

¹ MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Beijing Advanced Innovation Center for Structural Biology, School of Pharmaceutical Sciences, Tsinghua-Peking Center for Life Sciences, Center for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing, China.
² Key Laboratory of AIDS Immunology of National Health and Family Planning Commission, Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang, China.
³ School of System Biology, George Mason University, Manassas, VA, USA.
⁴ Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
⁵ Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
⁶ Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
⁷ Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, China.
⁸ Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
⁹ Beijing You'an Hospital, Capital Medical University, Beijing, China.
¹⁰ Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education and Institutes of Biomedical Sciences, Fudan University, Shanghai, China. [email protected].
¹¹ School of System Biology, George Mason University, Manassas, VA, USA. [email protected].
¹² MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Beijing Advanced Innovation Center for Structural Biology, School of Pharmaceutical Sciences, Tsinghua-Peking Center for Life Sciences, Center for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing, China. [email protected].

^# Contributed equally.

PMID: 30833724
DOI: 10.1038/s41564-019-0372-2

Abstract

Human immunodeficiency virus (HIV) actively modulates the protein stability of host cells to optimize viral replication. To systematically examine this modulation in HIV infection, we used isobaric tag-based mass spectrometry to quantify changes in the abundance of over 14,000 proteins during HIV-1 infection of human primary CD4⁺ T cells. We identified P-selectin glycoprotein ligand 1 (PSGL-1) as an HIV-1 restriction factor downregulated by HIV-1 Vpu, which binds to PSGL-1 and induces its ubiquitination and degradation through the ubiquitin ligase SCF^β-TrCP2. PSGL-1 is induced by interferon-γ in activated CD4⁺ T cells to inhibit HIV-1 reverse transcription and potently block viral infectivity by incorporating in progeny virions. This infectivity block is antagonized by Vpu via PSGL-1 degradation. We further show that PSGL-1 knockdown can significantly abolish the anti-HIV activity of interferon-γ in primary CD4⁺ T cells. Our study identifies an HIV restriction factor and a key mediator of interferon-γ's anti-HIV activity.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

CD4-Positive T-Lymphocytes / metabolism
CD4-Positive T-Lymphocytes / virology*
HIV Infections / genetics
HIV Infections / metabolism*
HIV Infections / physiopathology
HIV Infections / virology
HIV-1 / genetics
HIV-1 / physiology*
Host-Pathogen Interactions*
Human Immunodeficiency Virus Proteins / genetics
Human Immunodeficiency Virus Proteins / metabolism
Humans
Interferon-gamma / genetics
Interferon-gamma / metabolism
Membrane Glycoproteins / genetics
Membrane Glycoproteins / metabolism*
Proteolysis
Proteomics
SKP Cullin F-Box Protein Ligases / genetics
SKP Cullin F-Box Protein Ligases / metabolism
Ubiquitination
Viral Regulatory and Accessory Proteins / genetics
Viral Regulatory and Accessory Proteins / metabolism

Substances

Human Immunodeficiency Virus Proteins
Membrane Glycoproteins
P-selectin ligand protein
Viral Regulatory and Accessory Proteins
vpu protein, Human immunodeficiency virus 1
Interferon-gamma
SKP Cullin F-Box Protein Ligases

Grants and funding

R01 MH102144/MH/NIMH NIH HHS/United States