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SENP1 regulates IFN-γ−STAT1 signaling through STAT3−SOCS3 negative feedback loop Free
Tingting Yu1,2,3,†, Yong Zuo1,2,†, Rong Cai1,2,†, Xian Huang1,2, 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 Shen1,4,*, and Jinke Cheng1,2,3,*
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 *Correspondence to:Lei Shen, E-mail: lshen@shsmu.edu.cn; Jinke Cheng, E-mail: jkcheng@shsmu.edu.cn
J Mol Cell Biol, Volume 9, Issue 2, April 2017, 144-153,  https://doi.org/10.1093/jmcb/mjw042

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.


Volume 9, Issue 2
April 2017