title: SENP1 regulates IFN-γ-STAT1 signaling through STAT3-SOCS3 negative feedback loop.
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.
authors.affiliation: 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.|Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.|Department of Developmental Genetics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Yu
authors.affiliation: 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.|Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zuo
authors.affiliation: 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.|Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Cai
authors.affiliation: 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.|Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Xian
authors.initials: X
authors.lastname: Huang
authors.affiliation: Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Wu
authors.affiliation: Institute of Health Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Chenxi
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Institute of Health Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Y Eugene
authors.initials: YE
authors.lastname: Chin
authors.affiliation: 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.
authors.forename: Dongdong
authors.initials: D
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Zhenning
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Nansong
authors.initials: N
authors.lastname: Xia
authors.affiliation: 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.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Shen
authors.affiliation: Anhui Key Laboratory of Cellular Dynamics, Hefei National Laboratory for Physical Sciences at Nanoscale, University of Science and Technology of China, Hefei 230026, China.
authors.forename: Xuebiao
authors.initials: X
authors.lastname: Yao
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Zhong-Yin
authors.initials: ZY
authors.lastname: Zhang
authors.affiliation: Shanghai Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
authors.forename: Song
authors.initials: S
authors.lastname: Xue
authors.affiliation: 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.|Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Shen
authors.affiliation: 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.|Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.|Department of Developmental Genetics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Jinke
authors.initials: J
authors.lastname: Cheng
mesh_terms: D000818:Animals; D016764:Cell Polarity; D003546:Cysteine Endopeptidases; D010450:Endopeptidases / Q000172:deficiency / Q000378:metabolism*; D025461:Feedback, Physiological; D007371:Interferon-gamma / Q000378:metabolism*; D008089:Listeria monocytogenes / Q000502:physiology; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008954:Models, Biological; D010641:Phenotype; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D058207:Sumoylation; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000378:metabolism*
chemical_list: D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494080:Stat1 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D007371:Interferon-gamma; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; C501974:Senp1 protein, mouse
keywords: IFN-γ; SENP1; SUMOylation; macrophage