Abstract
RIPK1 (receptor-interacting serine/threonine-protein kinase 1) is a key molecule for mediating apoptosis, necroptosis, and inflammatory pathways downstream of death receptors (DRs) and pattern recognition receptors (PRRs). RIPK1 functions are regulated by multiple post-translational modifications (PTMs), including ubiquitination, phosphorylation, and the caspase-8-mediated cleavage. Dysregulation of these modifications leads to an immune deficiency or a hyperinflammatory disease in humans. Over the last decades, numerous studies on the RIPK1 function in model organisms have provided insights into the molecular mechanisms of RIPK1 role in the maintenance of immune homeostasis. However, the physiological role of RIPK1 in the regulation of cell survival and cell death signaling in humans remained elusive. Recently, RIPK1 loss-of-function (LoF) mutations and cleavage-deficient mutations have been identified in humans. This review discusses the molecular pathogenesis of RIPK1-deficiency and cleavage-resistant RIPK1 induced autoinflammatory (CRIA) disorders and summarizes the clinical manifestations of respective diseases to help with the identification of new patients.
Highlights
RIPK1 is a key modulator of inflammatory signaling and cell death pathways and its functions determine the cell fate upon different cellular stimulations
A growing body of evidence suggests that many human diseases, including systemic inflammation [1,2,3,4,5], cardiovascular disease [6], neurodegenerative disease [7], and cancer [8] are related to dysregulations in RIPK1-mediated cell death pathways
Besides the findings that mouse embryonic fibroblasts (MEFs) with RIPK1 non-cleavable mutants are sensitized to TNFinduced apoptosis and necroptosis, this study reports that caspase-8 mediated RIPK1 cleavage during embryogenesis can inhibit necroptosis and maintain normal development
Summary
RIPK1 is a key modulator of inflammatory signaling and cell death pathways and its functions determine the cell fate upon different cellular stimulations. RIPK1 deficiency due to pathogenic LoF variants leads to reduced NF-kB activation and dysregulated cell death under specific conditions, e.g., TNF or poly(I:C) stimulation, or a combination of TNF plus BV6 (IAP inhibitor) induced apoptosis and TNF, BV6 plus zVAD-fmk (pan-caspase inhibitor) induced necroptosis in patients’ fibroblasts, as well as in RIPK1-/- HT-29 cell lines [9, 10] (Figure 1C). The disease-associated variants Asp324Val, Asp324His, Asp324Asn, and Asp324Tyr were identified in different families either as a de novo mutation or as a dominantly inherited allele These pathogenic variants render RIPK1 non-cleavable, as they block caspase-8 mediated cleavage, thereby promoting RIPK1 activation. Both RIPK1-deficiency and CRIA patients present with a substantial dysregulation in inflammatory pathways and cytokine production.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
