The scaffold-dependent function of RIPK1 in dendritic cells promotes injury-induced colitis

Abstract

Receptor interacting protein kinase 1 (RIPK1) is a cytosolic multidomain protein that controls cell life and death. While RIPK1 promotes cell death through its kinase activity, it also functions as a scaffold protein to promote cell survival by inhibiting FADD-caspase 8-dependent apoptosis and RIPK3-MLKL-dependent necroptosis. This pro-survival function is highlighted by excess cell death and perinatal lethality in Ripk1−/− mice. Recently, loss of function mutation of RIPK1 was found in patients with immunodeficiency and inflammatory bowel diseases. Hematopoietic stem cell transplantation restored not only immunodeficiency but also intestinal inflammatory pathology, indicating that RIPK1 in hematopoietic cells is critical to maintain intestinal immune homeostasis. Here, we generated dendritic cell (DC)-specific Ripk1−/− mice in a genetic background with loss of RIPK1 kinase activity and found that the mice developed spontaneous colonic inflammation characterized by increased neutrophil and Ly6C+ monocytes. In addition, these mice were highly resistant to injury-induced colitis. The increased colonic inflammation and the resistance to colitis were restored by dual inactivation of RIPK3 and FADD, but not by inhibition of RIPK3, MLKL, or ZBP1 alone. Altogether, these results reveal a scaffold activity-dependent role of RIPK1 in DC-mediated maintenance of colonic immune homeostasis.

ZBP1: A Powerful Innate Immune Sensor and Double-Edged Sword in Host Immunity

“…RIPK1 E-KO mice (with the epidermis-specific RIPK1-knockout) suffer from skin inflammation because of ZBP1-dependent keratinocyte necroptosis [ 149 , 152 ]. The dendritic cell (DC)-specific RIPK1 −/− mice with loss of RIPK1 kinase activity in other cells, exhibit spontaneous colonic inflammation relied on ZBP1-RIPK3 necrosome [ 153 ]. Advanced research indicated that the Zα2 and RHIM1 of ZBP1 are vital for this RIPK1 −/− caused spontaneous necroptosis, and endogenous retroviruses (ERV)-derived complementary reads were detected in epidermal RNA [ 15 , 58 , 154 ] ( Figure 4 ).…”

Inhibition of RIPK1 kinase does not affect diabetes development: β-Cells survive RIPK1 activation

“…Our study showed no alteration in disease presentation in MLDSTZ- Ripk1 S25D/S25D compared to MLDSTZ- Ripk1 +/+ and RIPK1 enzymatic activation was not detected in islets of hyperglycemic mice subjected to MLDSTZ, demonstrating that RIPK1 kinase had no relevance in the dynamics of immune-mediated diabetes development. This lack of phenotype may reflect other studies which showed that dysfunctional immune responses were related to aberrant RIPK1 (prosurvival) scaffold function, independent of kinase activity [ 21 , 22 ].…”

A novel necroptosis related gene signature and regulatory network for overall survival prediction in lung adenocarcinoma

“…Complex II activates caspase-8 activation and promotes apoptosis 36 . RIPK1 acts as a scaffolding www.nature.com/scientificreports/ protein that inhibits apoptosis in FADD-caspase8-dependent cells and RIPK3-MLKL-dependent cells and promotes cell survival 46 .…”