Universität zu Köln

Lapacz, Kim J ORCID: 0000-0002-2494-4124, Weiss, Konstantin ORCID: 0000-0003-4895-9459, Mueller, Franziska ORCID: 0000-0002-4880-9269, Xue, Yuxing, Poepsel, Simon ORCID: 0000-0002-8304-4062, Weith, Matthias ORCID: 0000-0003-0804-4262, Bange, Tanja ORCID: 0000-0002-9680-8586 and Riemer, Jan ORCID: 0000-0002-7574-8457 (2025). DPP8/9 processing of human AK2 unmasks an IAP binding motif. EMBO Reports, 26 (11). pp. 2819-2835. Springer Nature. ISSN 1469-3178

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Abstract

Adenylate kinase 2 (AK2) is localized in the intermembrane space of mitochondria, where it ensures efficient adenine nucleotide exchange between cytosol and mitochondria. For mitochondrial import, AK2 relies on the MIA40 disulphide relay system. Its cytosolic stability is subject to regulation through N-terminal processing by the dipeptidyl peptidases DPP8 and DPP9, which sensitize AK2 for proteasomal degradation. Here, we find that cytosolic AK2 degradation is mediated by Inhibitors of Apoptosis (IAPs), a class of E3 ligases that interacts with target proteins by binding to IAP‐binding motifs (IBM). We have identified an IBM at the very end of AK2’s novel N‐terminus, which becomes exposed due to processing by DPP8/9. N‐terminal acetylation mediated by the N‐acetyltransferase NatA prevents this AK2-IAP interaction, therefore stabilizing AK2 in the cytosol. Performing a genome-wide in silico screen, we could identify 129 potential substrates in which an IBM becomes potentially unmasked by DPP8/9 processing. For one of these potential substrates, EIF2A, we demonstrate its targeting to IAPs after IBM exposure by DPP8/9 indicating that DPP8/9-mediated unmasking of IBMs is a general phenomenon.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Lapacz, Kim J UNSPECIFIED https://orcid.org/0000-0002-2494-4124 UNSPECIFIED Weiss, Konstantin UNSPECIFIED https://orcid.org/0000-0003-4895-9459 UNSPECIFIED Mueller, Franziska UNSPECIFIED https://orcid.org/0000-0002-4880-9269 UNSPECIFIED Xue, Yuxing UNSPECIFIED UNSPECIFIED UNSPECIFIED Poepsel, Simon UNSPECIFIED https://orcid.org/0000-0002-8304-4062 UNSPECIFIED Weith, Matthias UNSPECIFIED https://orcid.org/0000-0003-0804-4262 UNSPECIFIED Bange, Tanja UNSPECIFIED https://orcid.org/0000-0002-9680-8586 UNSPECIFIED Riemer, Jan UNSPECIFIED https://orcid.org/0000-0002-7574-8457 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-802121
Identification Number:	10.1038/s44319-025-00455-z
Journal or Publication Title:	EMBO Reports
Volume:	26
Number:	11
Page Range:	pp. 2819-2835
Number of Pages:	17
Date:	1 May 2025
Publisher:	Springer Nature
ISSN:	1469-3178
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences Faculty of Medicine
Divisions:	CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Biochemistry Zentrum für Molekulare Medizin
Subjects:	Life sciences Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language AK2 ; DPP9 ; Inhibitor of Apoptosis (IAP) Proteins ; N-terminal Acetylation ; IAP‐binding Motif English
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/80212