PRMT5-mediated regulatory arginine methylation of RIPK3
Abstract The TNF receptor-interacting protein kinases (RIPK)-1 and 3 are regulators of extrinsic cell death response pathways, where RIPK1 makes the cell survival or death decisions by associating with distinct complexes mediating survival signaling, caspase activation or RIPK3-dependent necroptotic...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-01-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-023-01299-z |
| _version_ | 1797946024956788736 |
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| author | Chanchal Chauhan Ana Martinez-Val Rainer Niedenthal Jesper Velgaard Olsen Alexey Kotlyarov Simon Bekker-Jensen Matthias Gaestel Manoj B. Menon |
| author_facet | Chanchal Chauhan Ana Martinez-Val Rainer Niedenthal Jesper Velgaard Olsen Alexey Kotlyarov Simon Bekker-Jensen Matthias Gaestel Manoj B. Menon |
| author_sort | Chanchal Chauhan |
| collection | DOAJ |
| description | Abstract The TNF receptor-interacting protein kinases (RIPK)-1 and 3 are regulators of extrinsic cell death response pathways, where RIPK1 makes the cell survival or death decisions by associating with distinct complexes mediating survival signaling, caspase activation or RIPK3-dependent necroptotic cell death in a context-dependent manner. Using a mass spectrometry-based screen to find new components of the ripoptosome/necrosome, we discovered the protein-arginine methyltransferase (PRMT)-5 as a direct interaction partner of RIPK1. Interestingly, RIPK3 but not RIPK1 was then found to be a target of PRMT5-mediated symmetric arginine dimethylation. A conserved arginine residue in RIPK3 (R486 in human, R415 in mouse) was identified as the evolutionarily conserved target for PRMT5-mediated symmetric dimethylation and the mutations R486A and R486K in human RIPK3 almost completely abrogated its methylation. Rescue experiments using these non-methylatable mutants of RIPK3 demonstrated PRMT5-mediated RIPK3 methylation to act as an efficient mechanism of RIPK3-mediated feedback control on RIPK1 activity and function. Therefore, this study reveals PRMT5-mediated RIPK3 methylation as a novel modulator of RIPK1-dependent signaling. |
| first_indexed | 2024-04-10T21:05:27Z |
| format | Article |
| id | doaj.art-842e471da4e14b86910bc06814c7448e |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-04-10T21:05:27Z |
| publishDate | 2023-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-842e471da4e14b86910bc06814c7448e2023-01-22T12:04:53ZengNature Publishing GroupCell Death Discovery2058-77162023-01-01911910.1038/s41420-023-01299-zPRMT5-mediated regulatory arginine methylation of RIPK3Chanchal Chauhan0Ana Martinez-Val1Rainer Niedenthal2Jesper Velgaard Olsen3Alexey Kotlyarov4Simon Bekker-Jensen5Matthias Gaestel6Manoj B. Menon7Institute of Cell Biochemistry, Hannover Medical SchoolMass Spectrometry for Quantitative Proteomics, Proteomics Program, The Novo Nordisk Foundation Center for Protein Research, University of CopenhagenInstitute of Cell Biochemistry, Hannover Medical SchoolMass Spectrometry for Quantitative Proteomics, Proteomics Program, The Novo Nordisk Foundation Center for Protein Research, University of CopenhagenInstitute of Cell Biochemistry, Hannover Medical SchoolCenter for Healthy Aging, Department of Cellular and Molecular Medicine, University of CopenhagenInstitute of Cell Biochemistry, Hannover Medical SchoolKusuma School of Biological Sciences, Indian Institute of Technology DelhiAbstract The TNF receptor-interacting protein kinases (RIPK)-1 and 3 are regulators of extrinsic cell death response pathways, where RIPK1 makes the cell survival or death decisions by associating with distinct complexes mediating survival signaling, caspase activation or RIPK3-dependent necroptotic cell death in a context-dependent manner. Using a mass spectrometry-based screen to find new components of the ripoptosome/necrosome, we discovered the protein-arginine methyltransferase (PRMT)-5 as a direct interaction partner of RIPK1. Interestingly, RIPK3 but not RIPK1 was then found to be a target of PRMT5-mediated symmetric arginine dimethylation. A conserved arginine residue in RIPK3 (R486 in human, R415 in mouse) was identified as the evolutionarily conserved target for PRMT5-mediated symmetric dimethylation and the mutations R486A and R486K in human RIPK3 almost completely abrogated its methylation. Rescue experiments using these non-methylatable mutants of RIPK3 demonstrated PRMT5-mediated RIPK3 methylation to act as an efficient mechanism of RIPK3-mediated feedback control on RIPK1 activity and function. Therefore, this study reveals PRMT5-mediated RIPK3 methylation as a novel modulator of RIPK1-dependent signaling.https://doi.org/10.1038/s41420-023-01299-z |
| spellingShingle | Chanchal Chauhan Ana Martinez-Val Rainer Niedenthal Jesper Velgaard Olsen Alexey Kotlyarov Simon Bekker-Jensen Matthias Gaestel Manoj B. Menon PRMT5-mediated regulatory arginine methylation of RIPK3 Cell Death Discovery |
| title | PRMT5-mediated regulatory arginine methylation of RIPK3 |
| title_full | PRMT5-mediated regulatory arginine methylation of RIPK3 |
| title_fullStr | PRMT5-mediated regulatory arginine methylation of RIPK3 |
| title_full_unstemmed | PRMT5-mediated regulatory arginine methylation of RIPK3 |
| title_short | PRMT5-mediated regulatory arginine methylation of RIPK3 |
| title_sort | prmt5 mediated regulatory arginine methylation of ripk3 |
| url | https://doi.org/10.1038/s41420-023-01299-z |
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