![]() In addition, RIPK1 harbors the RIP homotypic interaction motif (RHIM) in the intermediate region. ![]() RIPK1 consists of a kinase domain (KD) and a death domain (DD) at the N- and C-termini respectively. 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. Altogether, these results reveal a scaffold activity-dependent role of RIPK1 in DC-mediated maintenance of colonic immune homeostasis. 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. In addition, these mice were highly resistant to injury-induced colitis. 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. 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. ![]() Recently, loss of function mutation of RIPK1 was found in patients with immunodeficiency and inflammatory bowel diseases. This pro-survival function is highlighted by excess cell death and perinatal lethality in Ripk1 −/− mice. 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. Receptor interacting protein kinase 1 (RIPK1) is a cytosolic multidomain protein that controls cell life and death.
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