ReviewRegulatory mechanisms of RIPK1 in cell death and inflammation
Introduction
Cell death is an important strategy employed by multicellular organisms to maintain tissue homeostasis and to defend against pathogen challenge. Members of the Receptor Interacting Protein Kinases (RIPKs) family are key regulators of cell death and inflammation. Recent studies showed that RIPK1 is a pleiotropic cell death adaptor that not only control apoptosis and necroptosis but also directly regulate inflammatory cytokine expression. In contrast to apoptosis, which is generally non-inflammatory and tolerogenic, lytic cell death such as necroptosis promotes inflammation. Necroptosis and other types of lytic cell death such as pyroptosis and ferroptosis are marked by cell swelling and rapid loss of plasma membrane integrity. Membrane rupture leads to the release of cellular contents such as IL1α, HMGB1, uric acid, ATP and DNA into the extracellular space. Because these cellular components are potent stimulants for inflammation, they have been referred to as “damage-associated molecular patterns” (DAMPs). Because of the prominent roles of RIPK1 and its associate kinase RIPK3 in cell death and inflammation, extensive work has been done in recent years to decipher the molecular mechanisms that regulate their activities. These regulatory processes are diverse in nature (e.g. post-translational modifications versus protein-protein interactions). Collectively, they tune the functions of these kinases to maintain tissue homeostasis and to promote functional differentiation of immune cells. As such, disease ensues when these regulatory processes are disrupted. Here, we will review recent findings on the mechanisms that regulate RIPK1 activities.
Section snippets
A ubiquitin scaffold restricts RIPK1 death-inducing activity
The biochemical events that regulate RIPK1 activity is best studied in TNFR1 signaling. TNF binding to its cognate receptor TNFR1 induces formation of a membrane signaling complex termed complex I [1]. RIPK1 is recruited to this complex via death domain (DD)-DD interaction with the cytoplasmic tail of the receptor. RIPK1 is heavily ubiquitinated in this complex. In addition to RIPK1, another DD-containing adaptor TRADD also binds to TNFR1. TRADD recruitment to complex I promotes RIPK1
RHIM-mediated sequestration of RIPK1
The RHIM is defined by a highly conserved tetra-peptide core (e.g. IQIG or VQVG) flanked by mostly hydrophobic residues. The four mammalian RHIM-containing adaptors, RIPK1, RIPK3, the toll-like receptor 3 (TLR3)/TLR4 adaptor TRIF and the nucleic acid sensing adaptor ZBP1, are all critical signal adaptors for innate inflammation and cell death. In necroptosis, RIPK3 can be activated through RHIM-mediated binding with any of the other RHIM adaptors. This has led to the notion that RHIM-mediated
Concluding remarks
Our understanding of RIPK1 biology has undergone a major paradigm shift in recent years. It is now clear that RIPK1 is the fulcrum that balances cell survival and cell death signals. We argue that the different inhibitory mechanisms on RIPK1 have evolved to sense pathogen challenges. RIPK1 and the other RHIM signal adaptors share critical functions in innate immunity. Immune cells such as macrophages are often targeted by invading pathogens. Thus, interference of these sensor mechanisms will
Acknowledgement
This work is supported by NIH grant AI119030 and AI148302 (USA).
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2022, Nuclear Medicine and BiologyCitation Excerpt :Emerging evidence suggests that RIPK1 is involved in both apoptosis and necroptosis signal regulation of inflammatory cytokines. It plays an essential role in a variety of pathological and physiological processes [2]. In RIPK1-dependent necroptosis and inflammatory signaling, the carboxyl-terminus of RIPK1 contains the death domain that interacts with tumor necrosis factor receptor 1 (TNFR1) and triggers the assembly of Complex Ι, promoting the expression of a wide range of prosurvival and proinflammatory cytokines through nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling [3–5].
Tumor-intrinsic and immune modulatory roles of receptor-interacting protein kinases
2022, Trends in Biochemical SciencesCitation Excerpt :Necroptosis is widely considered to be a form of immunogenic cell death due to the release of damage-associated molecular patterns (DAMPs). However, early studies showed that overexpression of RIPK1 and RIPK3 could both stimulate the inflammatory transcription factor NF-κB (reviewed in [78]), indicating that the RIPKs can also directly stimulate proinflammatory cytokine expression independent of cell death [79] (Figure 2). In support of this, RNA-sequencing analysis of the colorectal cancer cell line HT-29 revealed that the RIPK1-RIPK3-MLKL axis facilitates NF-κB and p38-dependent inflammatory cytokine expression [80].
The latest information on the RIPK1 post-translational modifications and functions
2021, Biomedicine and PharmacotherapyCitation Excerpt :RIPK1 (671 amino acids) is composed of 86 Ser/Thr residues, but not all these sites are activated [49]. Multiple phosphorylation sites in RIPK1 were identified in early studies by mass spectrometry, and currently known phosphorylation sites that have been studied are mainly serine residues, namely, Ser6, Ser14, Ser15, Ser20, Ser25, Ser89, Ser109, Ser161, Ser166, Ser262, Ser296, Ser303, Ser313, Ser320, Ser330/331, Ser333, Ser335, Ser357, Ser416, Thr 189, and Thr 395 [8,10,38,41,50–56](Fig. 2a). Some of these residues do not seem to play functional roles because their phosphorylation does not change RIPK1 activity [54]; however, other sites are key for RIPK1 activation.