Protease-independent control of parthanatos by HtrA2/Omi.

Jonas Weiß, Michelle Heib, Thiemo Korn, Justus Hoyer, Johaiber Fuchslocher Chico, Susann Voigt, Tomas Koudelka, Andreas Tholey, Dieter Adam

Cellular and molecular life sciences : CMLS 2023 Aug 18

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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. © 2023. The Author(s).

Citation

Jonas Weiß, Michelle Heib, Thiemo Korn, Justus Hoyer, Johaiber Fuchslocher Chico, Susann Voigt, Tomas Koudelka, Andreas Tholey, Dieter Adam. Protease-independent control of parthanatos by HtrA2/Omi. Cellular and molecular life sciences : CMLS. 2023 Aug 18;80(9):258