The kinase domain of RIPK3 tunes its scaffolding functions
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ABSTRACT The pro-inflammatory programmed cell death pathway, necroptosis, relies on phosphorylation of the terminal effector, MLKL, by RIPK3. RIPK3-deficient mice or those harboring the kinase-inactivating mutation, RIPK3 K51A , are ostensibly normal in the absence of challenge, indicating that RIPK3 and its kinase activity are dispensable for development. However, another kinase-inactivating mutation, RIPK3 D161N , results in embryonic lethality in mice due to widespread apoptosis. As a result, the RIPK3 D161N mutation is thought to confer a toxic gain-of-function. Here, to further explore the impacts of RIPK3 inactivation, we compared the stability and cellular interactions of RIPK3 D161N and RIPK3 K51A to a third previously-uncharacterized kinase-dead variant, RIPK3 D143N . Here, we show that RIPK3 K51A was unstable and did not associate with RIPK1, RIPK3 D161N was unstable but interacted with RIPK1, whereas RIPK3 D143N was stable and bound RIPK1 in a manner comparable to wild-type RIPK3. Thus, all three variants scaffold differently, suggesting that the assembly of cell death machinery by RIPK3 is finely tuned, not just by its kinase activity, but also by the conformation of its kinase domain. Physiologically, Ripk3 D143N/D143N mice exhibited a partially penetrant lethality in utero . However, once born, Ripk3 D143N/D143N mice were fertile and phenotypically indistinguishable from wild-type mice in the absence of challenge, with RIPK3 D143N mutation protecting mice lacking intestinal epithelial Caspase-8 from necroptotic ileitis. Our studies support the idea that RIPK3 is a nexus between apoptotic and necroptotic signaling, and highlight the importance of considering kinase domain conformation in RIPK3 inhibitor development.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- The kinase domain of RIPK3 tunes its scaffolding functions
- Date Crossref
- 29/04/2025
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
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The University of Melbourne Department of Medical Biology pays non établi dans la noticeUniversité ou école supérieure
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Walter and Eliza Hall Institute of Medical Research pays non établi dans la noticeOrganisation à but non lucratif
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The Royal Melbourne Hospital pays non établi dans la noticeOrganisme public
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Monash University Monash Institute of Pharmaceutical Sciences pays non établi dans la noticeUniversité ou école supérieure
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La Trobe University pays non établi dans la noticeUniversité ou école supérieure
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Olivia Newton-John Cancer Wellness & Research Centre pays non établi dans la noticeÉtablissement de santé
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Olivia Newton-John Cancer Research Institute pays non établi dans la noticeOrganisation à but non lucratif
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School of Cancer Medicine pays non établi dans la noticeUniversité ou école supérieure
Department of Medical Biology — The University of Melbourne, Walter and Eliza Hall Institute of Medical Research et The Royal Melbourne Hospital, avec 5 autres affiliations.
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