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.
Highlights
Receptor interacting protein kinase 1 (RIPK1) is a cytosolic serine/ threonine kinase that functions downstream of various cell surface immune-related receptors such as tumor necrosis factor receptor 1 (TNFR1)[1]
Because Ki67high population among colonic CD11c+ dendritic cell (DC) was normal in CD11c;Ripk1kd/kd mice (Fig. S3), the decreased kinase activity-dependent and -independent roles in DCs, we crossed Ripk[1] kinase-dead mutant knock-in mice (Ripk1kd/kd)[29], in which exon 4 was flanked by loxP sequences, with CD11c-Cre transgenic mice (CD11c;Ripk1kd/kd mice)
MLN CD8α+ resident DCs were not changed in CD11c;Ripk1kd/kd mice, which is similar to the spleen
Summary
Receptor interacting protein kinase 1 (RIPK1) is a cytosolic serine/ threonine kinase that functions downstream of various cell surface immune-related receptors such as tumor necrosis factor receptor 1 (TNFR1)[1]. In the membrane-bound TNFR1 complex, called complex I, RIPK1 is modified by K63- and M1-ubiquitination by the action of cellular inhibitor of apoptosis 1 (cIAP1) and linear ubiquitin chain assembly complex (LUBAC)[2] These ubiquitin chains on RIPK1 act as a scaffold to recruit various signaling kinases such as an inhibitor of κB kinase (IKK) α/β, IKKε, transforming growth factor β activated kinase 1 (TAK1), and TANK binding kinase 1 (TBK1)[3]. IKKs phosphorylate inhibitor of κB (IκB), leading to NF-κB-dependent expression of pro-survival molecules such as cellular FLICE inhibitory protein (cFLIP)[4] When these kinases are inhibited, RIPK1 interacts with FADD and caspase 8 to induce RIPK1-dependent apoptosis. This RIPK1-indepenent apoptosis is potentiated by loss of RIPK1 through diminished induction of pro-survival gene expression
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