RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis

Abstract

Necroptosis has emerged as an important pathway of programmed cell death in embryonic development, tissue homeostasis, immunity and inflammation1–8. RIPK1 is implicated in inflammatory and cell death signalling9–13 and its kinase activity is believed to drive RIPK3-mediated necroptosis14,15. Here we show that kinase-independent scaffolding RIPK1 functions regulate homeostasis and prevent inflammation in barrier tissues by inhibiting epithelial cell apoptosis and necroptosis. Intestinal epithelial cell (IEC)-specific RIPK1 knockout caused IEC apoptosis, villus atrophy, loss of goblet and Paneth cells and premature death in mice. This pathology developed independently of the microbiota and of MyD88 signalling but was partly rescued by TNFR1 (also known as TNFRSF1A) deficiency. Epithelial FADD ablation inhibited IEC apoptosis and prevented the premature death of mice with IEC-specific RIPK1 knockout. However, mice lacking both RIPK1 and FADD in IECs displayed RIPK3-dependent IEC necroptosis, Paneth cell loss and focal erosive inflammatory lesions in the colon. Moreover, a RIPK1 kinase inactive knock-in delayed but did not prevent inflammation caused by FADD deficiency in IECs or keratinocytes, showing that RIPK3-dependent necroptosis of FADD-deficient epithelial cells only partly requires RIPK1 kinase activity. Epidermis-specific RIPK1 knockout triggered keratinocyte apoptosis and necroptosis and caused severe skin inflammation that was prevented by RIPK3 but not FADD deficiency. These findings revealed that RIPK1 inhibits RIPK3-mediated necroptosis in keratinocytes in vivo and identified necroptosis as a more potent trigger of inflammation compared with apoptosis. Therefore, RIPK1 is a master regulator of epithelial cell survival, homeostasis and inflammation in the intestine and the skin.

TRAF2 is a biologically important necroptosis suppressor

“…Although access to detailed histopathological analysis was not available to us in this study, it is notable that the DKO phenotype bears similarity to that reported recently for selective RIPK1 KO in intestinal epithelial cells. [50][51][52] The latter involves kinaseindependent RIPK1 activity, which confers stabilization of several pro-survival proteins, including TRAF2, cIAPs and cFLIP. 52 It will be interesting to investigate whether TRAF2 is linked to the kinase-independent functions of RIPK1 and/or RIPK3.…”

“…[50][51][52] The latter involves kinaseindependent RIPK1 activity, which confers stabilization of several pro-survival proteins, including TRAF2, cIAPs and cFLIP. 52 It will be interesting to investigate whether TRAF2 is linked to the kinase-independent functions of RIPK1 and/or RIPK3.…”

Old, new and emerging functions of caspases

“…RIP1 functions to protect cells from excessive caspase-8-mediated apoptosis and TNF-driven inflammation to maintain cell homeostasis in barrier tissues such as the gut epithelium and skin. 28,29 Pyroptosis. Cell death by pyroptosis was first observed in macrophages following infection with Shigella flexneri or Salmonella typhimurium.…”

Exploration of immunogene in colon cancer recurrence

“…In particular, 12 of the 31 identified genes have been reported in the literatures to be related to colon cancer recurrence [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37], which can be regarded as validation to our prediction results for these 12 genes. For the other 19 genes identified by us, we cannot exclude the possibility that some of them are due to false positive prediction.…”