The Receptor Interacting Protein Kinases in the Liver

Abstract

The Receptor Interacting serine/threonine Kinase1 and 3 (RIPK1, RIPK3) are regulators of cell death and survival. RIPK1 kinase activity is required for necroptosis and apoptosis, while its scaffolding function is necessary for survival. Although both proteins can mediate apoptosis, RIPK1 and RIPK3 are most well-known for their role in the execution of necroptosis via the pseudokinase mixed lineage domain like (MLKL). Necroptosis is a caspase-independent regulated cell death program which was first described in cultured cells with unknown physiologic relevance in the liver. Many recent reports have suggested that RIPK1 and/or RIPK3 participate in liver disease pathogenesis and cell death. Notably, both proteins have been shown to mediate inflammation independent of cell death. Whether necroptosis occurs in hepatocytes, and how it is executed in the presence of an intact caspase machinery is controversial. In spite of this controversy, it is evident that RIPK1 and RIPK3 participate in many experimental liver disease models. Therefore, in addition to cell death signaling, their necroptosis independent role warrants further examination.

MicroRNA-378 promotes hepatic inflammation and fibrosis via modulation of the NF-κB-TNFα pathway

“…S5D). 35 In addition to promoting inflammation, 36 1L6 can induce expression of Tgfb1, a key cytokine involved in the pathogenesis of fibrosis. 37 Indeed, both protein and mRNA levels of Tgfbl and Timpl in livers of HFD-treated mice were significantly increased after miR-378 treatment (Fig.…”

Necroptotic Cell Death in Liver Transplantation and Underlying Diseases: Mechanisms and Clinical Perspective

“…Generally, TNF‐α can trigger the formation of prosurvival‐ and proinflammatory‐related complexes and caspase‐dependent apoptosis . Specifically, TNFR1 recruits TNFR1‐associated death domain (TRADD) protein, tumor necrosis factor receptor–associated factor 2 (TRAF2), receptor‐interacting serine/threonine‐protein kinase (RIPK) 1, cellular inhibitor of apoptosis protein (cIAP) 1/2, and the linear ubiquitin chain assembly complex (LUBAC) to form the complex I, which contributes to the activation of the NF‐κB signaling pathway . After dissociation from TNFR1, complex I will be transformed into complex IIa (comprising TRADD, Fas‐associated protein with death domain [FADD], FLICE‐inhibitory protein [FLIP], and procaspase 8), leading to activation of caspase 8 and rendering RIPK1‐independent apoptosis .…”

“…(7) Specifically, TNFR1 recruits TNFR1-associated death domain (TRADD) protein, tumor necrosis factor receptor-associated factor 2 (TRAF2), receptorinteracting serine/threonine-protein kinase (RIPK) 1, cellular inhibitor of apoptosis protein (cIAP) 1/2, and the linear ubiquitin chain assembly complex (LUBAC) to form the complex I, which contributes to the activation of the NF-κB signaling pathway. (8) After dissociation from TNFR1, complex I will be transformed into complex IIa (comprising TRADD, Fas-associated protein with death domain [FADD], FLICE-inhibitory protein [FLIP], and procaspase 8), leading to activation of caspase 8 and rendering RIPK1-independent apoptosis. (9) Conversely, the formation of complex IIb, consisting of RIPK1, RIPK3, FADD, FLIPs, and caspase 8, can be promoted by knockdown of the nuclear factor kappa B Review ARticle | 1093 essential modulator (NEMO), blockage of cIAPs, or transforming growth factor β-activated kinase 1 (TAK1).…”

Novel Drivers of the Inflammatory Response in Liver Injury and Fibrosis

“…63,64 A recent review by Dara summarizes the growing body of evidence that the RIPKs are multifunctional proteins with prominent roles independent of their actions as cell death mediators. 65 In summary, the contribution of necroptosis on acute liver injury seems rather limited while studies point to a potential relevant role in chronic liver injury models. However, an important limitation of most of the described studies is that they have all been performed using global RIPK3 or MLKL knockout mice, and thus cannot distinguish between intrinsic hepatocyte mechanisms and systemic effects particularly on the immune system.…”