Evolutionary and functional analyses reveal a role for the RHIM in tuning RIPK3 activity across vertebrates
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 la...
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eLife Sciences Publications Ltd
2025-05-01
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| Online Access: | https://elifesciences.org/articles/102301 |
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| author | Elizabeth J Fay Kolya Isterabadi Charles M Rezanka Jessica Le Matthew D Daugherty |
| author_facet | Elizabeth J Fay Kolya Isterabadi Charles M Rezanka Jessica Le Matthew D Daugherty |
| author_sort | Elizabeth J Fay |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-1944b4ae1d4c40b498e1aad1e78b12cd |
| institution | OA Journals |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-05-01 |
| publisher | eLife Sciences Publications Ltd |
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| series | eLife |
| spelling | doaj-art-1944b4ae1d4c40b498e1aad1e78b12cd2025-08-20T02:30:23ZengeLife Sciences Publications LtdeLife2050-084X2025-05-011310.7554/eLife.102301Evolutionary and functional analyses reveal a role for the RHIM in tuning RIPK3 activity across vertebratesElizabeth J Fay0https://orcid.org/0000-0003-1712-757XKolya Isterabadi1Charles M Rezanka2Jessica Le3Matthew D Daugherty4https://orcid.org/0000-0002-4879-9603Department of Molecular Biology, School of Biological Sciences, University of California, San Diego, La Jolla, United StatesDepartment of Molecular Biology, School of Biological Sciences, University of California, San Diego, La Jolla, United StatesDepartment of Molecular Biology, School of Biological Sciences, University of California, San Diego, La Jolla, United StatesDepartment of Molecular Biology, School of Biological Sciences, University of California, San Diego, La Jolla, United StatesDepartment of Molecular Biology, School of Biological Sciences, University of California, San Diego, La Jolla, United StatesReceptor 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.https://elifesciences.org/articles/102301innate immunityRIP kinasesNF-kBvertebrate evolution |
| spellingShingle | Elizabeth J Fay Kolya Isterabadi Charles M Rezanka Jessica Le Matthew D Daugherty Evolutionary and functional analyses reveal a role for the RHIM in tuning RIPK3 activity across vertebrates eLife innate immunity RIP kinases NF-kB vertebrate evolution |
| title | Evolutionary and functional analyses reveal a role for the RHIM in tuning RIPK3 activity across vertebrates |
| title_full | Evolutionary and functional analyses reveal a role for the RHIM in tuning RIPK3 activity across vertebrates |
| title_fullStr | Evolutionary and functional analyses reveal a role for the RHIM in tuning RIPK3 activity across vertebrates |
| title_full_unstemmed | Evolutionary and functional analyses reveal a role for the RHIM in tuning RIPK3 activity across vertebrates |
| title_short | Evolutionary and functional analyses reveal a role for the RHIM in tuning RIPK3 activity across vertebrates |
| title_sort | evolutionary and functional analyses reveal a role for the rhim in tuning ripk3 activity across vertebrates |
| topic | innate immunity RIP kinases NF-kB vertebrate evolution |
| url | https://elifesciences.org/articles/102301 |
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