SENP1 regulates IFN-γ-STAT1 signaling through STAT3-SOCS3 negative feedback loop

Tingting Yu; Yong Zuo; Rong Cai; Xian Huang; Shuai Wu; Chenxi Zhang; Y Eugene Chin; Dongdong Li; Zhenning Zhang; Nansong Xia; Qi Wang; Hao Shen; Xuebiao Yao; Zhong-Yin Zhang; Song Xue; Lei Shen; Jinke Cheng

doi:10.1093/jmcb/mjw042

SENP1 regulates IFN-γ-STAT1 signaling through STAT3-SOCS3 negative feedback loop

J Mol Cell Biol. 2017 Apr 1;9(2):144-153. doi: 10.1093/jmcb/mjw042.

Authors

Tingting Yu^{1

2

3}, Yong Zuo^{1

2}, Rong Cai^{1

2}, Xian Huang^{1

2}, Shuai Wu⁴, Chenxi Zhang⁵, Y Eugene Chin⁵, Dongdong Li¹, Zhenning Zhang¹, Nansong Xia¹, Qi Wang¹, Hao Shen⁶, Xuebiao Yao⁷, Zhong-Yin Zhang⁸, Song Xue⁹, Lei Shen^{1

4}, Jinke Cheng^{1

2

3}

Affiliations

¹ Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
² Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
³ Department of Developmental Genetics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China.
⁴ Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
⁵ Institute of Health Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
⁶ Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁷ Anhui Key Laboratory of Cellular Dynamics, Hefei National Laboratory for Physical Sciences at Nanoscale, University of Science and Technology of China, Hefei 230026, China.
⁸ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
⁹ Shanghai Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.

Abstract

Interferon-γ (IFN-γ) triggers macrophage for inflammation response by activating the intracellular JAK-STAT1 signaling. Suppressor of cytokine signaling 1 (SOCS1) and protein tyrosine phosphatases can negatively modulate IFN-γ signaling. Here, we identify a novel negative feedback loop mediated by STAT3-SOCS3, which is tightly controlled by SENP1 via de-SUMOylation of protein tyrosine phosphatase 1B (PTP1B), in IFN-γ signaling. SENP1-deficient macrophages show defects in IFN-γ signaling and M1 macrophage activation. PTP1B in SENP1-deficient macrophages is highly SUMOylated, which reduces PTP1B-induced de-phosphorylation of STAT3. Activated STAT3 then suppresses STAT1 activation via SOCS3 induction in SENP1-deficient macrophages. Accordingly, SENP1-deficient macrophages show reduced ability to resist Listeria monocytogenes infection. These results reveal a crucial role of SENP1-controlled STAT1 and STAT3 balance in macrophage polarization.

Keywords: IFN-γ; SENP1; SUMOylation; macrophage.

MeSH terms

Animals
Cell Polarity
Cysteine Endopeptidases
Endopeptidases / deficiency
Endopeptidases / metabolism*
Feedback, Physiological*
Interferon-gamma / metabolism*
Listeria monocytogenes / physiology
Macrophages / metabolism
Macrophages / microbiology
Mice
Models, Biological
Phenotype
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
STAT1 Transcription Factor / metabolism*
STAT3 Transcription Factor / metabolism*
Signal Transduction*
Sumoylation
Suppressor of Cytokine Signaling 3 Protein / metabolism*

Substances

STAT1 Transcription Factor
STAT3 Transcription Factor
Socs3 protein, mouse
Stat1 protein, mouse
Suppressor of Cytokine Signaling 3 Protein
Interferon-gamma
Protein Tyrosine Phosphatase, Non-Receptor Type 1
Ptpn1 protein, mouse
Endopeptidases
Cysteine Endopeptidases
Senp1 protein, mouse

Grants and funding

R01 CA207288/CA/NCI NIH HHS/United States