Abstract
Cell death and inflammation are closely linked arms of the innate immune response to combat infection and tissue malfunction. Recent advancements in our understanding of the intricate signals originating from dying cells have revealed that cell death serves as more than just an end point. It facilitates the exchange of information between the dying cell and cells of the tissue microenvironment, particularly immune cells, alerting and recruiting them to the site of disturbance. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is emerging as a critical stress sentinel that functions as a molecular switch, governing cellular survival, inflammatory responses and immunogenic cell death signalling. Its tight regulation involves multiple layers of post-translational modifications. In this Review, we discuss the molecular mechanisms that regulate RIPK1 to maintain homeostasis and cellular survival in healthy cells, yet drive cell death in a context-dependent manner. We address how RIPK1 mutations or aberrant regulation is associated with inflammatory and autoimmune disorders and cancer. Moreover, we tease apart what is known about catalytic and non-catalytic roles of RIPK1 and discuss the successes and pitfalls of current strategies that aim to target RIPK1 in the clinic.
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Acknowledgements
The authors apologize to all the authors whose work we could not cite in this Review owing to space limitations. The authors thank T. Kaserer and E. Stefan for discussions and the design of Fig. 3. Furthermore, the authors thank members of the Meier Laboratory for helpful discussions and critical reading of the manuscript. Particularly, the authors would like to thank A. Legrand for discussion and input. J.C. is funded by Breast Cancer Now, Catalyst Grant Research Funding Scheme, which is supported by Pfizer (2017JulyPCC004) and Cancer Research UK (A24399). P.M. is supported by Cancer Research UK (A24399) and Breast Cancer Now (CTR-R14–007). The authors acknowledge NHS funding to the NIHR biomedical Research Centre.
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COSMIC database: https://cancer.sanger.ac.uk/cosmic
Glossary
- Alarmins
-
A specific class of danger signals or damage-associated molecular patterns (DAMPs) that are released during immunogenic cell death.
- Cyclic GMP–AMP synthase
-
A cytosolic DNA sensor that is involved in the detection of viral and cellular DNA.
- Damage-associated molecular patterns
-
(DAMPs). Molecules that are released by cells when they are damaged or stressed and function to alert the immune system to the presence of danger.
- Immune checkpoint blockade
-
(ICB). A type of immunotherapy that targets and prevents immune checkpoint proteins from inactivating an immune response against cancer cells.
- Immunogenic cell death
-
A type of cell death that results in the release of specific molecules (called ‘danger signals’ or ‘damage-associated molecular patterns (DAMPs)) that can activate the immune system.
- Interferon
-
(IFN). A group of antiviral glycoprotein cytokines that provide host protection by inducing expression of antiviral effector molecules that are encoded by IFN-stimulated genes.
- Mitogen-activated protein kinases
-
(MAPKs). A family of serine and threonine protein kinases that have a critical role in intracellular signalling pathways that control cell growth, differentiation and survival.
- NOD-like receptors
-
(NLRs). Highly conserved cytoplasmic receptors containing a nucleotide-binding and oligomerization domain and belong to the pattern recognition receptor (PRR) family and have a key role in innate immunity by detecting intracellular microbial breach intracellularly.
- Nuclear factor-κB
-
(NF-κB). A transcription factor that has a critical role in regulating the immune and inflammatory response.
- Toll-like receptors
-
(TLRs). A group of transmembrane receptors that act as a first line of defence against microorganisms by recognizing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) and subsequently inducing pro-inflammatory responses. TLR2 belongs to the pattern recognition receptor (PRR) family.
- Z-RNA-binding protein 1
-
(ZBP1, also known as DAI). A nucleic acid sensor that detects Z-DNA and Z-RNA and mediates pro-inflammatory responses and programmed cell death.
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Clucas, J., Meier, P. Roles of RIPK1 as a stress sentinel coordinating cell survival and immunogenic cell death. Nat Rev Mol Cell Biol 24, 835–852 (2023). https://doi.org/10.1038/s41580-023-00623-w
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DOI: https://doi.org/10.1038/s41580-023-00623-w
