RIPK1-Associated Inborn Errors of Innate Immunity

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.

A common humanMLKLpolymorphism confers resistance to negative regulation by phosphorylation

“…Consistent with this notion, more than 20 unique disease-associated human germline gene variants in the core necroptotic machinery, encompassing RIPK1, RIPK3, MLKL, have been identified (Garnish and Hildebrand, 2022;Zhang et al, 2021). In one family, a haplotype including a rare MLKL loss-of-function gene variant (p.Asp369GlufsTer22, rs561839347) is associated with a severe and progressive novel neurogenerative spectrum disorder characterized by global brain atrophy (Faergeman et al, 2020).…”

Rare catastrophes and evolutionary legacies: human germline gene variants in MLKL and the necroptosis signalling pathway

“…One patient also suffered from growth restriction, severe motor delay and mild intellectual disability [ 70 ]. An increased susceptibility to viral, bacterial and fungal infection was also reported [ 53 , 71 ]. Patient fibroblasts isolated from one of these patients were shown to be more susceptible to cell death in the presence of TNF and polyI:C. These cells were protected from death by the MLKL inhibitor necrosulfonamide, strongly implicating necroptosis [ 68 ].…”

“…Based on observations of important MLKL regulatory genes gleaned from genetically modified mice [ 20 ], we have plotted for the purposes of this review the number of disease associated human mutations reported in ClinVar [ 52 ], as accessed in September 2021 ( Figure 2A ). This tally is strongly dominated by RIPK1 , TNFAIP3 (encoding A20) and CASP8 , where several unique LOF or missense mutations are characterised by autoinflammatory and lymphoproliferative syndromes [ 53 ]. It is important to note however, that the identification of pathogenic gene variants is heavily biased towards those that associated with severe or atypical disease.…”

Break down the barriers of auto‐inflammation: How to deal with a monogenic auto‐inflammatory disease and immuno‐haematological features in 2022?

“…RIPK1 is a key determinant of cell response to TNF stimulation (Figure 2). Its ubiquitination status shifts the cell towards either a pro-survival inflammatory pathway via NF-κB activation, or cell death pathway via activation of caspase-8-dependent apoptosis or RIPK3/ MLKL-dependent necroptosis [52]. RIPK1 deficiency, due to homozygous RIPK1 LOF mutation, leads to reduced NF-κB activity, increased NLRP3 inflammasome activity and impaired T-cell and B-cell development.…”