2. Academic Validation
  3. c-Jun N-terminal kinases differentially regulate TNF- and TLRs-mediated necroptosis through their kinase-dependent and -independent activities

c-Jun N-terminal kinases differentially regulate TNF- and TLRs-mediated necroptosis through their kinase-dependent and -independent activities

  • Cell Death Dis. 2018 Nov 15;9(12):1140. doi: 10.1038/s41419-018-1189-2.
Mengtao Cao 1 2,  Fei Chen 3 4,  Ni Xie 3,  Meng-Yao Cao 5,  Pengfei Chen 3,  Qi Lou 3 4,  Yanli Zhao 3,  Chen He 6,  Shuyuan Zhang 7,  Xinyang Song 8,  Yu Sun 4,  Weimin Zhu 9,  Lisha Mou 3,  Shaodong Luan 7,  Hanchao Gao 10 11
Affiliations

Affiliations

  • 1 Institute of Transformation Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen University School of Medicine, 518300, Shenzhen, China. mtcao@sibs.ac.cn.
  • 2 The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Science, 200031, Shanghai, China. mtcao@sibs.ac.cn.
  • 3 Institute of Transformation Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen University School of Medicine, 518300, Shenzhen, China.
  • 4 The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Science, 200031, Shanghai, China.
  • 5 Department of Radiology, The People's Hospital of Tongliang District, 402560, Chongqing, China.
  • 6 Department of Ophthalmology, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, 518035, Shenzhen, Guangdong, China.
  • 7 Department of Nephrology, Shenzhen Longhua District Central Hospital, Guangdong Medical University Affiliated Longhua District Central Hospital, 518300, Shenzhen, China.
  • 8 Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, 02115, USA.
  • 9 Department of Sports Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, 518035, Shenzhen, Guangdong, China.
  • 10 Institute of Transformation Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen University School of Medicine, 518300, Shenzhen, China. hcgao@foxmail.com.
  • 11 Department of Nephrology, Shenzhen Longhua District Central Hospital, Guangdong Medical University Affiliated Longhua District Central Hospital, 518300, Shenzhen, China. hcgao@foxmail.com.
PMID: 30442927 DOI: 10.1038/s41419-018-1189-2
Abstract

Tumor necrosis factor (TNF) and Toll-like Receptor (TLR)3/TLR4 activation trigger necroptotic cell death through downstream signaling complex containing receptor-interacting protein kinase 1 (RIPK1), RIPK3, and pseudokinase mixed lineage kinase-domain-like (MLKL). However, the regulation of necroptotic signaling pathway is far less investigated. Here we showed that c-Jun N-terminal kinases (JNK1 and JNK2) displayed kinase-dependent and -independent functions in regulating TNF- and TLRs-mediated Necroptosis. We found that RIPK1 and RIPK3 promoted cell-death-independent JNK activation in macrophages, which contributed to pro-inflammatory cytokines production. Meanwhile, blocking the kinase activity of JNK dramatically reduced TNF and TLRs-induced necroptotic cell death. Consistently, inhibition of JNK activity protected mice from TNF-induced death and Staphylococcus aureus-mediated lung damage. However, depletion of JNK protein using siRNA sensitized macrophages to Necroptosis that was triggered by LPS or poly I:C but still inhibited TNF-induced Necroptosis. Mechanistic studies revealed that RIPK1 recruited JNK to the necrosome complex and their kinase activity was required for necrosome formation and the phosphorylation of MLKL in TNF- and TLRs-induced Necroptosis. Loss of JNK protein consistently suppressed the phosphorylation of MLKL and necrosome formation in TNF-triggered Necroptosis, but differentially promoted the phosphorylation of MLKL and necrosome formation in poly I:C-triggered Necroptosis by promoting the oligomeration of TRIF. In conclusion, our findings define a differential role for JNK in regulating TNF- and TLRs-mediated Necroptosis by their kinase or scaffolding activities.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z