Saita, Shotaro ORCID: 0000-0002-7406-8361, Nolte, Hendrik, Fiedler, Kai Uwe, Kashkar, Hamid, Venne, A. Saskia, Zahedi, Rene P., Krueger, Marcus and Langer, Thomas (2017). PARL mediates Smac proteolytic maturation in mitochondria to promote apoptosis. Nat. Cell Biol., 19 (4). S. 318 - 355. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-4679

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Abstract

Mitochondria drive apoptosis by releasing pro-apoptotic proteins that promote caspase activation in the cytosol. The rhomboid protease PARL, an intramembrane cleaving peptidase in the inner membrane, regulates mitophagy and plays an ill-defined role in apoptosis. Here, we employed PARL-based proteomics to define its substrate spectrum. Our data identified the mitochondrial pro-apoptotic protein Smac (also known as DIABLO) as a PARL substrate. In apoptotic cells, Smac is released into the cytosol and promotes caspase activity by inhibiting inhibitors of apoptosis (IAPs). Intramembrane cleavage of Smac by PARL generates an amino-terminal IAP-binding motif, which is required for its apoptotic activity. Loss of PARL impairs proteolytic maturation of Smac, which fails to bind XIAP. Smac peptidomimetics, downregulation of XIAP or cytosolic expression of cleaved Smac restores apoptosis in PARL-deficient cells. Our results reveal a pro-apoptotic function of PARL and identify PARL-mediated Smac processing and cytochrome c release facilitated by OPA1-dependent cristae remodelling as two independent pro-apoptotic pathways in mitochondria.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Saita, ShotaroUNSPECIFIEDorcid.org/0000-0002-7406-8361UNSPECIFIED
Nolte, HendrikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fiedler, Kai UweUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kashkar, HamidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Venne, A. SaskiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zahedi, Rene P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krueger, MarcusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Langer, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-236051
DOI: 10.1038/ncb3488
Journal or Publication Title: Nat. Cell Biol.
Volume: 19
Number: 4
Page Range: S. 318 - 355
Date: 2017
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1476-4679
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CYTOCHROME-C RELEASE; M-AAA PROTEASE; 3-METHYLGLUTACONIC ACIDURIA; OPA1; FUSION; XIAP; MUTATIONS; CLPB; OMA1; IDENTIFICATIONMultiple languages
Cell BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/23605

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