HIV-1 Nef-associated Factor 1 Enhances Viral Production by Interacting with CRM1 to Promote Nuclear Export of Unspliced HIV-1 gag mRNA

Xiao-Xin Ren; Hai-Bo Wang; Chuan Li; Jin-Feng Jiang; Si-Dong Xiong; Xia Jin; Li Wu; Jian-Hua Wang

doi:10.1074/jbc.M115.706135

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HIV-1 Nef-associated Factor 1 Enhances Viral Production by Interacting with CRM1 to Promote Nuclear Export of Unspliced HIV-1 gag mRNA

Journal article

Open access

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HIV-1 Nef-associated Factor 1 Enhances Viral Production by Interacting with CRM1 to Promote Nuclear Export of Unspliced HIV-1 gag mRNA

Xiao-Xin Ren, Hai-Bo Wang, Chuan Li, Jin-Feng Jiang, Si-Dong Xiong, Xia Jin, Li Wu and Jian-Hua Wang

The Journal of biological chemistry, Vol.291(9), pp.4580-4588

02/26/2016

DOI: 10.1074/jbc.M115.706135

PMCID: PMC4813482

PMID: 26733199

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Abstract

HIV-1 depends on host-cell-encoded factors to complete its life cycle. A comprehensive understanding of how HIV-1 manipulates host machineries during viral infection can facilitate the identification of host targets for antiviral drugs or gene therapy. The cellular protein Naf1 (HIV-1 Nef-associated factor 1) is a CRM1-dependent nucleo-cytoplasmic shuttling protein, and has been identified to regulate multiple receptor-mediated signal pathways in inflammation. The cytoplasm-located Naf1 can inhibit NF-κB activation through binding to A20, and the loss of Naf1 controlled NF-κB activation is associated with multiple autoimmune diseases. However, the effect of Naf1 on HIV-1 mRNA expression has not been characterized. In this study we found that the nucleus-located Naf1 could promote nuclear export of unspliced HIV-1 gag mRNA. We demonstrated that the association between Naf1 and CRM1 was required for this function as the inhibition or knockdown of CRM1 expression significantly impaired Naf1-promoted HIV-1 production. The mutation of Naf1 nuclear export signals (NESs) that account for CRM1 recruitment for nuclear export decreased Naf1 function. Additionally, the mutation of the nuclear localization signal (NLS) of Naf1 diminished its ability to promote HIV-1 production, demonstrating that the shuttling property of Naf1 is required for this function. Our results reveal a novel role of Naf1 in enhancing HIV-1 production, and provide a potential therapeutic target for controlling HIV-1 infection.

Immunoprecipitation

Nuclear Localization Signals - genetics

Humans

Green Fluorescent Proteins - genetics

RNA, Messenger - metabolism

Recombinant Fusion Proteins - metabolism

DNA-Binding Proteins - metabolism

gag Gene Products, Human Immunodeficiency Virus - metabolism

HIV-1 - physiology

RNA Interference

HEK293 Cells

Carrier Proteins - chemistry

RNA Precursors - metabolism

RNA, Viral - metabolism

gag Gene Products, Human Immunodeficiency Virus - genetics

Green Fluorescent Proteins - metabolism

DNA-Binding Proteins - antagonists & inhibitors

RNA Transport

Cell Survival

Carrier Proteins - antagonists & inhibitors

Nuclear Localization Signals - metabolism

gag Gene Products, Human Immunodeficiency Virus - antagonists & inhibitors

Receptors, Cytoplasmic and Nuclear - genetics

Recombinant Fusion Proteins - chemistry

DNA-Binding Proteins - genetics

DNA-Binding Proteins - chemistry

Carrier Proteins - genetics

Microscopy, Confocal

Point Mutation

Carrier Proteins - metabolism

Karyopherins - metabolism

Nuclear Export Signals

Virus Replication

Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors

Karyopherins - genetics

Karyopherins - antagonists & inhibitors

Receptors, Cytoplasmic and Nuclear - metabolism

Details

Title: Subtitle: HIV-1 Nef-associated Factor 1 Enhances Viral Production by Interacting with CRM1 to Promote Nuclear Export of Unspliced HIV-1 gag mRNA
Creators: Xiao-Xin Ren - From the Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China, Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China, and
Hai-Bo Wang - Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China, and
Chuan Li - Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China, and
Jin-Feng Jiang - Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China, and
Si-Dong Xiong - From the Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China
Xia Jin - Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China, and
Li Wu - Center for Retrovirus Research, Department of Veterinary Biosciences, Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio 43210
Jian-Hua Wang - Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China, and jh_wang@sibs.ac.cn
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.291(9), pp.4580-4588
DOI: 10.1074/jbc.M115.706135
PMID: 26733199
PMCID: PMC4813482
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: United States
Grant note: R01 AI104483 / NIAID NIH HHS AI104483 / NIAID NIH HHS R01 AI120209 / NIAID NIH HHS AI120209 / NIAID NIH HHS
Language: English
Date published: 02/26/2016
Academic Unit: Microbiology and Immunology
Record Identifier: 9984001122802771

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