Fay Elizabeth J, Isterabadi Kolya, Rezanka Charles M, Le Jessica, Daugherty Matthew D
Department of Molecular Biology, School of Biological Sciences, University of California, San Diego, La Jolla, United States.
Elife. 2025 May 28;13:RP102301. doi: 10.7554/eLife.102301.
Receptor interacting protein kinases (RIPK) RIPK1 and RIPK3 play important roles in diverse innate immune pathways. Despite this, some RIPK1/3-associated proteins are absent in specific vertebrate lineages, suggesting that some RIPK1/3 functions are conserved, while others are more evolutionarily labile. Here, we perform comparative evolutionary analyses of RIPK1-5 and associated proteins in vertebrates to identify lineage-specific rapid evolution of RIPK3 and RIPK1 and recurrent loss of RIPK3-associated proteins. Despite this, diverse vertebrate RIPK3 proteins are able to activate NF-κB and cell death in human cells. Additional analyses revealed a striking conservation of the RIP homotypic interaction motif (RHIM) in RIPK3, as well as other human RHIM-containing proteins. Interestingly, diversity in the RIPK3 RHIM can tune activation of NF-κB while retaining the ability to activate cell death. Altogether, these data suggest that NF-κB activation is a core, conserved function of RIPK3, and the RHIM can tailor RIPK3 function to specific needs within and between species.
受体相互作用蛋白激酶（RIPK）RIPK1和RIPK3在多种先天性免疫途径中发挥重要作用。尽管如此，一些RIPK1/3相关蛋白在特定脊椎动物谱系中并不存在，这表明一些RIPK1/3功能是保守的，而另一些则在进化上更不稳定。在这里，我们对脊椎动物中的RIPK1-5及相关蛋白进行了比较进化分析，以确定RIPK3和RIPK1的谱系特异性快速进化以及RIPK3相关蛋白的反复丢失。尽管如此，多种脊椎动物的RIPK3蛋白能够在人类细胞中激活NF-κB并导致细胞死亡。进一步分析发现，RIPK3中的RIP同型相互作用基序（RHIM）以及其他含人类RHIM的蛋白具有显著的保守性。有趣的是，RIPK3 RHIM的多样性可以调节NF-κB的激活，同时保留激活细胞死亡的能力。总之，这些数据表明NF-κB激活是RIPK3的核心保守功能，并且RHIM可以根据物种内部和物种之间的特定需求调整RIPK3的功能。
