Regulation of RIPK1 Phosphorylation: Implications for Inflammation, Cell Death, and Therapeutic Interventions

Overview

Journal Biomedicines

Specialty Biomedical Engineering

Date 2024 Jul 27

PMID 39062098

Authors

Jingchun Du

Zhigao Wang

Affiliations

Soon will be listed here.

Abstract

Receptor-interacting protein kinase 1 (RIPK1) plays a crucial role in controlling inflammation and cell death. Its function is tightly controlled through post-translational modifications, enabling its dynamic switch between promoting cell survival and triggering cell death. Phosphorylation of RIPK1 at various sites serves as a critical mechanism for regulating its activity, exerting either activating or inhibitory effects. Perturbations in RIPK1 phosphorylation status have profound implications for the development of severe inflammatory diseases in humans. This review explores the intricate regulation of RIPK1 phosphorylation and dephosphorylation and highlights the potential of targeting RIPK1 phosphorylation as a promising therapeutic strategy for mitigating human diseases.

Citing Articles

RIPK1 in necroptosis and recent progress in related pharmaceutics.

Yao K, Shi Z, Zhao F, Tan C, Zhang Y, Fan H Front Immunol. 2025; 16:1480027.

PMID: 40007541 PMC: 11850271. DOI: 10.3389/fimmu.2025.1480027.

References

Hincelin-Mery A, Nicolas X, Cantalloube C, Pomponio R, Lewanczyk P, Benamor M . Safety, pharmacokinetics, and target engagement of a brain penetrant RIPK1 inhibitor, SAR443820 (DNL788), in healthy adult participants. Clin Transl Sci. 2023; 17(1):e13690. PMC: 10772668. DOI: 10.1111/cts.13690. View

Lalaoui N, Boyden S, Oda H, Wood G, Stone D, Chau D . Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease. Nature. 2019; 577(7788):103-108. PMC: 6930849. DOI: 10.1038/s41586-019-1828-5. View

Zhang T, Xu D, Trefts E, Lv M, Inuzuka H, Song G . Metabolic orchestration of cell death by AMPK-mediated phosphorylation of RIPK1. Science. 2023; 380(6652):1372-1380. PMC: 10617018. DOI: 10.1126/science.abn1725. View

Wang H, Sun L, Su L, Rizo J, Liu L, Wang L . Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol Cell. 2014; 54(1):133-146. DOI: 10.1016/j.molcel.2014.03.003. View

McQuade T, Cho Y, Chan F . Positive and negative phosphorylation regulates RIP1- and RIP3-induced programmed necrosis. Biochem J. 2013; 456(3):409-15. PMC: 4143978. DOI: 10.1042/BJ20130860. View

Polykratis A, Hermance N, Zelic M, Roderick J, Kim C, Van T . Cutting edge: RIPK1 Kinase inactive mice are viable and protected from TNF-induced necroptosis in vivo. J Immunol. 2014; 193(4):1539-1543. PMC: 4119562. DOI: 10.4049/jimmunol.1400590. View

Kaiser W, Daley-Bauer L, Thapa R, Mandal P, Berger S, Huang C . RIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition. Proc Natl Acad Sci U S A. 2014; 111(21):7753-8. PMC: 4040608. DOI: 10.1073/pnas.1401857111. View

Mahoney D, Cheung H, Mrad R, Plenchette S, Simard C, Enwere E . Both cIAP1 and cIAP2 regulate TNFalpha-mediated NF-kappaB activation. Proc Natl Acad Sci U S A. 2008; 105(33):11778-83. PMC: 2575330. DOI: 10.1073/pnas.0711122105. View

Kanayama A, Seth R, Sun L, Ea C, Hong M, Shaito A . TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains. Mol Cell. 2004; 15(4):535-48. DOI: 10.1016/j.molcel.2004.08.008. View

10.

Shan B, Pan H, Najafov A, Yuan J . Necroptosis in development and diseases. Genes Dev. 2018; 32(5-6):327-340. PMC: 5900707. DOI: 10.1101/gad.312561.118. View

11.

Tu H, Xiong W, Zhang J, Zhao X, Lin X . Tyrosine phosphorylation regulates RIPK1 activity to limit cell death and inflammation. Nat Commun. 2022; 13(1):6603. PMC: 9632600. DOI: 10.1038/s41467-022-34080-4. View

12.

Cohen P . Protein phosphatase 1--targeted in many directions. J Cell Sci. 2002; 115(Pt 2):241-56. DOI: 10.1242/jcs.115.2.241. View

13.

Newton K, Wickliffe K, Dugger D, Maltzman A, Roose-Girma M, Dohse M . Cleavage of RIPK1 by caspase-8 is crucial for limiting apoptosis and necroptosis. Nature. 2019; 574(7778):428-431. DOI: 10.1038/s41586-019-1548-x. View

14.

Zheng Z, Deng W, Bai Y, Miao R, Mei S, Zhang Z . The Lysosomal Rag-Ragulator Complex Licenses RIPK1 and Caspase-8-mediated Pyroptosis by . Science. 2022; 372(6549). PMC: 8769499. DOI: 10.1126/science.abg0269. View

15.

Dondelinger Y, Delanghe T, Rojas-Rivera D, Priem D, Delvaeye T, Bruggeman I . MK2 phosphorylation of RIPK1 regulates TNF-mediated cell death. Nat Cell Biol. 2017; 19(10):1237-1247. DOI: 10.1038/ncb3608. View

16.

Du J, Xiang Y, Liu H, Liu S, Kumar A, Xing C . RIPK1 dephosphorylation and kinase activation by PPP1R3G/PP1γ promote apoptosis and necroptosis. Nat Commun. 2021; 12(1):7067. PMC: 8642546. DOI: 10.1038/s41467-021-27367-5. View

17.

Zou Y, Zheng Q, Jiang B, Liu Y, Xu Y, Ma L . Deficiency of PPP6C protects TNF-induced necroptosis through activation of TAK1. Cell Death Dis. 2022; 13(7):618. PMC: 9288536. DOI: 10.1038/s41419-022-05076-1. View

18.

Cuchet-Lourenco D, Eletto D, Wu C, Plagnol V, Papapietro O, Curtis J . Biallelic mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation. Science. 2018; 361(6404):810-813. PMC: 6529353. DOI: 10.1126/science.aar2641. View

19.

Demarco B, Grayczyk J, Bjanes E, Le Roy D, Tonnus W, Assenmacher C . Caspase-8-dependent gasdermin D cleavage promotes antimicrobial defense but confers susceptibility to TNF-induced lethality. Sci Adv. 2020; 6(47). PMC: 7673803. DOI: 10.1126/sciadv.abc3465. View

20.

Lin L, Wang Y, Liu L, Ying W, Wang W, Sun B . Clinical phenotype of a Chinese patient with RIPK1 deficiency due to novel mutation. Genes Dis. 2020; 7(1):122-127. PMC: 7063410. DOI: 10.1016/j.gendis.2019.10.008. View