USP4 interacts and positively regulates IRF8 function via K48-linked deubiquitination in regulatory T cells

Ruirong Lin; Jia Nie; Jiazi Ren; Rui Liang; Dan Li; Ping Wang; Chengjiang Gao; Changhua Zhuo; Chunkang Yang; Bin Li

doi:10.1002/1873-3468.12668

USP4 interacts and positively regulates IRF8 function via K48-linked deubiquitination in regulatory T cells

FEBS Lett. 2017 Jun;591(12):1677-1686. doi: 10.1002/1873-3468.12668. Epub 2017 Jun 7.

Authors

Ruirong Lin^{1

2

3}, Jia Nie², Jiazi Ren^{2

3}, Rui Liang^{2

3}, Dan Li^{2

3}, Ping Wang⁴, Chengjiang Gao⁵, Changhua Zhuo¹, Chunkang Yang¹, Bin Li^{2

3}

Affiliations

¹ Department of Gastrointestinal Surgical Oncology, Fujian Provincial Key Laboratory of Tumor Biotherapy, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, China.
² Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, China.
³ Key Laboratory of Molecular Virology & Immunology, CAS Center for Excellence in Molecular Cell Science, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences Medical School, Shanghai, China.
⁴ Department of Central Laboratory, School of Life Science and Technology, Shanghai Tenth People's Hospital of Tongji University, Tongji University, Shanghai, China.
⁵ Department of Immunology and Key Laboratory of Infection and Immunity of Shandong Province, Shandong University School of Basic Medical Sciences, Jinan, China.

PMID: 28477415
DOI: 10.1002/1873-3468.12668

Abstract

CD4⁺ CD25⁺ regulatory T (Treg) cells comprise a unique subset of T cells required for maintaining immune homeostasis. However, the molecular mechanisms associated with the functional variety of Treg cells are not fully delineated. In the present study, we demonstrate that ubiquitin-specific protease (USP)4 physically interacted with interferon regulatory factor 8 (IRF8) function via a K48-linked deubiquitinase, which stabilized IRF8 protein levels in Treg cells. Depletion of USP4 promoted the polyubiquitination of IRF8 and the upregulation of type 2 inflammatory cytokine gene expression in Treg cells. Consistently, treatment of Treg cells with USP4 inhibitor facilitated the polyubiquitination of IRF8. In addition, the deficiency of USP4 alleviated the suppressive function of Treg cells. Taken together, our results suggest that USP4 interacts with and stabilizes IRF8 to promote the suppressive function of Treg cells.

Keywords: IRF8; USP4; regulatory T cells.

Publication types

Comparative Study

MeSH terms

Amino Acid Substitution
Cells, Cultured
Enzyme Inhibitors / pharmacology
Gene Expression Regulation / drug effects
HEK293 Cells
Humans
Interferon Regulatory Factors / chemistry
Interferon Regulatory Factors / genetics
Interferon Regulatory Factors / metabolism*
Lysine / metabolism
Mutagenesis, Site-Directed
Mutation
Peptide Fragments / antagonists & inhibitors
Peptide Fragments / chemistry
Peptide Fragments / genetics
Peptide Fragments / metabolism
Protein Interaction Domains and Motifs
Protein Stability / drug effects
RNA Interference
Recombinant Fusion Proteins / chemistry
Recombinant Fusion Proteins / metabolism
T-Lymphocytes, Helper-Inducer / cytology
T-Lymphocytes, Helper-Inducer / drug effects
T-Lymphocytes, Helper-Inducer / immunology
T-Lymphocytes, Helper-Inducer / metabolism
T-Lymphocytes, Regulatory / cytology
T-Lymphocytes, Regulatory / drug effects
T-Lymphocytes, Regulatory / immunology
T-Lymphocytes, Regulatory / metabolism*
Ubiquitin-Specific Proteases / antagonists & inhibitors
Ubiquitin-Specific Proteases / chemistry
Ubiquitin-Specific Proteases / genetics
Ubiquitin-Specific Proteases / metabolism*
Ubiquitination / drug effects

Substances

Enzyme Inhibitors
Interferon Regulatory Factors
Peptide Fragments
Recombinant Fusion Proteins
USP4 protein, human
interferon regulatory factor-8
Ubiquitin-Specific Proteases
Lysine