c-Jun N-terminal kinases differentially regulate TNF- and TLRs-mediated necroptosis through their kinase-dependent and -independent activities.
Mengtao CaoFei ChenNi XieMeng-Yao CaoPengfei ChenQi LouYanli ZhaoChen HeShuyuan ZhangXinyang SongYu SunWeimin ZhuLisha MouShaodong LuanHanchao GaoPublished in: Cell death & disease (2018)
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.
Keyphrases
- cell death
- protein kinase
- signaling pathway
- rheumatoid arthritis
- toll like receptor
- induced apoptosis
- cell cycle arrest
- high glucose
- inflammatory response
- diabetic rats
- staphylococcus aureus
- pi k akt
- immune response
- oxidative stress
- epithelial mesenchymal transition
- drug induced
- nuclear factor
- mass spectrometry
- endoplasmic reticulum stress
- anti inflammatory
- escherichia coli
- high resolution
- small molecule
- cancer therapy
- insulin resistance
- adipose tissue
- atomic force microscopy
- biofilm formation