Complex Pathologic Roles of RIPK1 and RIPK3: Moving Beyond Necroptosis

Abstract

A process of regulated necrosis, termed necroptosis, has been recognized as a major contributor to cell death and inflammation occurring under a wide range of pathologic settings. The core event in necroptosis is the formation of the detergent-insoluble “necrosome” complex of homologous Ser/Thr kinases Receptor Interacting Kinase 1 (RIPK1) and Receptor Interacting Kinase 3 (RIPK3), which promotes phosphorylation of a key pro-death effector Mixed Lineage Kinase Domain-like (MLKL) by RIPK3. Core necroptosis mediators are under multiple controls, which have been a subject of intense investigation. Additional, non-necroptotic functions of these factors, primarily in controlling apoptosis and inflammatory responses, have also begun to emerge. This review will provide an overview of the current understanding of the human disease relevance of this pathway, and potential therapeutic strategies, targeting necroptosis mediators in various pathologies.

CETSA quantitatively verifies in vivo target engagement of novel RIPK1 inhibitors in various biospecimens

“…Receptor interacting protein 1 kinase (RIPK1) is a key mediator of not only a process of regulated necrosis, termed necroptosis, but also promotion of caspase-8-dependent apoptosis and pro-inflammatory gene expression 13 . Based on kinase-dead knock-in RIPK1 mice and highly selective allosteric Type 3 RIPK1 inhibitors (necrostatin-1 [Nec-1] and optimized analogue Nec-1s) 14,15 , RIPK1 is implicated in a variety of human diseases, such as ischemia-reperfusion injury in the brain 16 , heart 17 , and kidney 18 , acute and chronic inflammatory diseases 19 , multiple sclerosis (MS) 20 , and amyotrophic lateral sclerosis 21 .…”

RIPK1 promotes inflammation and β-amyloid accumulation in Alzheimer’s disease

“…Although RIPK1 is often thought of as a mediator of necroptosis, a form of necrotic cell death, it also promotes inflammation downstream of the TNFα receptor: mice carrying kinase-dead knock-in mutations in RIPK1 are protected against TNFα-induced inflammation (9). In this study, the authors implicate this latter proinflammatory role of RIPK1 in AD.…”

A Role for Receptor-Interacting Protein Kinase-1 in Neutrophil Extracellular Trap Formation in Patients with Systemic Lupus Erythematosus: a Preliminary Study

“…However, the role of these proteins also differ in a context-dependent manner. Many pathologies involving RIPK1 and RIPK3 are associated with acute or chronic inflammation as well as disruption of immune homeostasis [12]. The contribution of RIPK1 and RIPK3 kinases to inflammatory and autoimmune pathologies has been an area of major focus and has provided many interesting conclusions [14, 27, 28].…”

“…In our study, expression of RIPK1, RIPK3, and MLKL are low, specifically in neutrophils. Recent studies on proteins involved in necroptosis signaling (RIPK1, RIPK3, MLKL, cFLIP) suggest that suppression of inflammation or cell death involves RIPK1 [12, 31, 32]. …”