Ripk1, also known as receptor-interacting serine/threonine-protein kinase 1, is a key mediator of cell death (including apoptosis and necroptosis) and inflammation [1,2,4,5]. It is involved in pathways downstream of death receptors like the tumour necrosis factor (TNF) receptor superfamily and pattern recognition receptors. Its functions are regulated by post-translational modifications such as ubiquitination, phosphorylation, and caspase-8-mediated cleavage. Genetic models, especially KO/CKO mouse models, have been crucial for studying its functions [3,5].

Ripk1-deficient mice die soon after birth, highlighting its essential role in normal development [3]. In neurodegenerative diseases such as multiple sclerosis, amyotrophic lateral sclerosis (ALS), Parkinson's disease, and Alzheimer's disease, Ripk1-mediated necroptosis promotes cell death and neuroinflammation [1]. In ALS, loss of optineurin leads to axonal degeneration through RIPK1-RIPK3-MLKL-mediated necroptosis [6]. In COPD, RIPK1 expression increases in certain lung cell types, and genetic or pharmacological inhibition of its kinase activity attenuates airway inflammation, remodelling, and cell death [5].

In conclusion, Ripk1 is a critical regulator of cell death and inflammation. Studies using KO/CKO mouse models have revealed its role in neurodegenerative diseases like ALS and in respiratory diseases such as COPD. Understanding Ripk1's functions provides potential therapeutic targets for these and other related diseases.

References:

1. Yuan, Junying, Amin, Palak, Ofengeim, Dimitry. . Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases. In Nature reviews. Neuroscience, 20, 19-33. doi:10.1038/s41583-018-0093-1. https://pubmed.ncbi.nlm.nih.gov/30467385/

2. Degterev, Alexei, Ofengeim, Dimitry, Yuan, Junying. 2019. Targeting RIPK1 for the treatment of human diseases. In Proceedings of the National Academy of Sciences of the United States of America, 116, 9714-9722. doi:10.1073/pnas.1901179116. https://pubmed.ncbi.nlm.nih.gov/31048504/

3. Newton, Kim. 2015. RIPK1 and RIPK3: critical regulators of inflammation and cell death. In Trends in cell biology, 25, 347-53. doi:10.1016/j.tcb.2015.01.001. https://pubmed.ncbi.nlm.nih.gov/25662614/

4. Mifflin, Lauren, Ofengeim, Dimitry, Yuan, Junying. 2020. Receptor-interacting protein kinase 1 (RIPK1) as a therapeutic target. In Nature reviews. Drug discovery, 19, 553-571. doi:10.1038/s41573-020-0071-y. https://pubmed.ncbi.nlm.nih.gov/32669658/

5. Van Eeckhoutte, Hannelore P, Donovan, Chantal, Kim, Richard Y, Hansbro, Philip M, Bracke, Ken R. 2023. RIPK1 kinase-dependent inflammation and cell death contribute to the pathogenesis of COPD. In The European respiratory journal, 61, . doi:10.1183/13993003.01506-2022. https://pubmed.ncbi.nlm.nih.gov/36549711/

6. Ito, Yasushi, Ofengeim, Dimitry, Najafov, Ayaz, Ravits, John, Yuan, Junying. . RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS. In Science (New York, N.Y.), 353, 603-8. doi:10.1126/science.aaf6803. https://pubmed.ncbi.nlm.nih.gov/27493188/