TY - JOUR
T1 - DeSUMOylation of MKK7 kinase by the SUMO2/3 protease SENP3 potentiates lipopolysaccharide-induced inflammatory signaling in macrophages
AU - Lao, Yimin
AU - Yang, Kai
AU - Wang, Zhaojun
AU - Sun, Xueqing
AU - Zou, Qiang
AU - Yu, Xiaoyan
AU - Cheng, Jinke
AU - Tong, Xuemei
AU - Yeh, Edward T.H.
AU - Yang, Jie
AU - Yi, Jing
N1 - Funding Information:
This work was supported by National Natural Science Foundation of China Grants 31230037 and 31471263, Ministry of Science and Technology of China Grant 2013CB910900, and the Ministry of Education of China Grant 20130073110002. The authors declare that they have no conflicts of inter-est with the contents of this article. Author’s Choice—Final version free via Creative Commons CC-BY license. This article contains Figs. S1–S3. 1 To whom correspondence may be addressed. E-mail: yangjieyj@shsmu.edu.cn. 2To whom correspondence may be addressed: Dept. of Biochemistry and Molecular Cell Biology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 S. Chongqing Rd., Shanghai 200025, China. E-mail: yijing@shsmu.edu.cn.
Funding Information:
This work was supported by National Natural Science Foundation of China Grants 31230037 and 31471263, Ministry of Science and Technology of China Grant 2013CB910900, and the Ministry of Education of China Grant 20130073110002. The authors declare that they have no conflicts of interest with the contents of this article.
Publisher Copyright:
© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2018/3/16
Y1 - 2018/3/16
N2 - Protein SUMOylation has been reported to play a role in innate immune response, but the enzymes, substrates, and consequences of the specific inflammatory signaling events are largely unknown. Reactive oxygen species (ROS) are abundantly produced during macrophage activation and required for Toll-like receptor 4 (TLR4)-mediated inflammatory signaling. Previously, we demonstrated that SENP3 is a redox-sensitive SUMO2/3 protease. To explore any links between reversible SUMOylation and ROS-related inflammatory signaling in macrophage activation, we generated mice with Senp3 conditional knock-out in myeloid cells. In bacterial lipopolysaccharide (LPS)-induced in vitro and in vivo inflammation models, we found that SENP3 deficiency markedly compromises the activation of TLR4 inflammatory signaling and the production of proinflammatory cytokines in macrophages exposed to LPS. Moreover, Senp3 conditional knock-out mice were significantly less susceptible to septic shock. Of note, SENP3 deficiency was associated with impairment in JNK phosphorylation. We found that MKK7, which selectively phosphorylates JNK, is a SENP3 substrate and that SENP3-mediated deSUMOylation of MKK7 may favor its binding to JNK. Importantly, ROS-dependent SENP3 accumulation and MKK7 deSUMOylation rapidly occurred after LPS stimulation. In conclusion, our findings indicate that SENP3 potentiates LPS-induced TLR4 signaling via deSUMOylation of MKK7 leading to enhancement in JNK phosphorylation and the downstream events. Therefore this work provides novel mechanistic insights into redox regulation of innate immune responses.
AB - Protein SUMOylation has been reported to play a role in innate immune response, but the enzymes, substrates, and consequences of the specific inflammatory signaling events are largely unknown. Reactive oxygen species (ROS) are abundantly produced during macrophage activation and required for Toll-like receptor 4 (TLR4)-mediated inflammatory signaling. Previously, we demonstrated that SENP3 is a redox-sensitive SUMO2/3 protease. To explore any links between reversible SUMOylation and ROS-related inflammatory signaling in macrophage activation, we generated mice with Senp3 conditional knock-out in myeloid cells. In bacterial lipopolysaccharide (LPS)-induced in vitro and in vivo inflammation models, we found that SENP3 deficiency markedly compromises the activation of TLR4 inflammatory signaling and the production of proinflammatory cytokines in macrophages exposed to LPS. Moreover, Senp3 conditional knock-out mice were significantly less susceptible to septic shock. Of note, SENP3 deficiency was associated with impairment in JNK phosphorylation. We found that MKK7, which selectively phosphorylates JNK, is a SENP3 substrate and that SENP3-mediated deSUMOylation of MKK7 may favor its binding to JNK. Importantly, ROS-dependent SENP3 accumulation and MKK7 deSUMOylation rapidly occurred after LPS stimulation. In conclusion, our findings indicate that SENP3 potentiates LPS-induced TLR4 signaling via deSUMOylation of MKK7 leading to enhancement in JNK phosphorylation and the downstream events. Therefore this work provides novel mechanistic insights into redox regulation of innate immune responses.
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U2 - 10.1074/jbc.M117.816769
DO - 10.1074/jbc.M117.816769
M3 - Article
C2 - 29352108
AN - SCOPUS:85044141898
SN - 0021-9258
VL - 293
SP - 3965
EP - 3980
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 11
ER -