Article ; Online: Protease-independent control of parthanatos by HtrA2/Omi.
Cellular and molecular life sciences : CMLS
2023 Volume 80, Issue 9, Page(s) 258
Abstract: HtrA2/Omi is a mitochondrial serine protease with ascribed pro-apoptotic as well as pro-necroptotic functions. Here, we establish that HtrA2/Omi also controls parthanatos, a third modality of regulated cell death. Deletion of HtrA2/Omi protects cells ... ...
| Abstract | HtrA2/Omi is a mitochondrial serine protease with ascribed pro-apoptotic as well as pro-necroptotic functions. Here, we establish that HtrA2/Omi also controls parthanatos, a third modality of regulated cell death. Deletion of HtrA2/Omi protects cells from parthanatos while reconstitution with the protease restores the parthanatic death response. The effects of HtrA2/Omi on parthanatos are specific and cannot be recapitulated by manipulating other mitochondrial proteases such as PARL, LONP1 or PMPCA. HtrA2/Omi controls parthanatos in a manner mechanistically distinct from its action in apoptosis or necroptosis, i.e., not by cleaving cytosolic IAP proteins but rather exerting its effects without exiting mitochondria, and downstream of PARP-1, the first component of the parthanatic signaling cascade. Also, previously identified or candidate substrates of HtrA2/Omi such as PDXDC1, VPS4B or moesin are not cleaved and dispensable for parthanatos, whereas DBC-1 and stathmin are cleaved, and thus represent potential parthanatic downstream mediators of HtrA2/Omi. Moreover, mass-spectrometric screening for novel parthanatic substrates of HtrA2/Omi revealed that the induction of parthanatos does not cause a substantial proteolytic cleavage or major alterations in the abundance of mitochondrial proteins. Resolving these findings, reconstitution of HtrA2/Omi-deficient cells with a catalytically inactive HtrA2/Omi mutant restored their sensitivity against parthanatos to the same level as the protease-active HtrA2/Omi protein. Additionally, an inhibitor of HtrA2/Omi's protease activity did not confer protection against parthanatic cell death. Our results demonstrate that HtrA2/Omi controls parthanatos in a protease-independent manner, likely via novel, unanticipated functions as a scaffolding protein and an interaction with so far unknown mitochondrial proteins. |
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| MeSH term(s) | Parthanatos ; Serine Proteases/genetics ; Necroptosis ; Serine Endopeptidases/genetics ; Mitochondrial Proteins/genetics |
| Chemical Substances | Serine Proteases (EC 3.4.-) ; Serine Endopeptidases (EC 3.4.21.-) ; Mitochondrial Proteins |
| Language | English |
| Publishing date | 2023-08-18 |
| Publishing country | Switzerland |
| Document type | Journal Article |
| ZDB-ID | 1358415-7 |
| ISSN | 1420-9071 ; 1420-682X |
| ISSN (online) | 1420-9071 |
| ISSN | 1420-682X |
| DOI | 10.1007/s00018-023-04904-7 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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