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Autophosphorylation and Pin1 binding coordinate DNA damage-induced HIPK2 activation and cell death

Excessive genome damage activates the apoptosis response. Protein kinase HIPK2 is a key regulator of DNA damage-induced apoptosis. Here, we deciphered the molecular mechanism of HIPK2 activation and show its relevance for DNA damage-induced apoptosis in cellulo and in vivo. HIPK2 autointeracts and s...

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Main Authors: Bitomsky, Nadja (Author) , Conrad, Elisa (Author) , Moritz, Christian (Author) , Polonio-Vallon, Tilman (Author) , Sombroek, Dirk (Author) , Schultheiß, Kathrin (Author) , Glas, Carolina (Author) , Greiner, Vera (Author) , Herbel, Christoph (Author) , Mantovani, Fiamma (Author) , Sal, Giannino del (Author) , Peri, Francesca (Author) , Hofmann, Thomas G. (Author)
Format: Article (Journal)
Language:English
Published: October 21, 2013
In: Proceedings of the National Academy of Sciences of the United States of America
Year: 2013, Volume: 110, Issue: 45, Pages: E4203-E4212
ISSN:1091-6490
DOI:10.1073/pnas.1310001110
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1073/pnas.1310001110
Verlag, lizenzpflichtig, Volltext: https://www.pnas.org/content/110/45/E4203
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Author Notes:Nadja Bitomsky, Elisa Conrad, Christian Moritz, Tilman Polonio-Vallon, Dirk Sombroek, Kathrin Schultheiss, Carolina Glas, Vera Greiner, Christoph Herbel, Fiamma Mantovani, Giannino del Sal, Francesca Peri, and Thomas G. Hofmann
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Summary:Excessive genome damage activates the apoptosis response. Protein kinase HIPK2 is a key regulator of DNA damage-induced apoptosis. Here, we deciphered the molecular mechanism of HIPK2 activation and show its relevance for DNA damage-induced apoptosis in cellulo and in vivo. HIPK2 autointeracts and site-specifically autophosphorylates upon DNA damage at Thr880/Ser882. Autophosphorylation regulates HIPK2 activity and mutation of the phosphorylation-acceptor sites deregulates p53 Ser46 phosphorylation and apoptosis in cellulo. Moreover, HIPK2 autophosphorylation is conserved between human and zebrafish and is important for DNA damage-induced apoptosis in vivo. Mechanistically, autophosphorylation creates a binding signal for the phospho-specific isomerase Pin1. Pin1 links HIPK2 activation to its stabilization by inhibiting HIPK2 polyubiquitination and modulating Siah-1-HIPK2 interaction. Concordantly, Pin1 is required for DNA damage-induced HIPK2 stabilization and p53 Ser46 phosphorylation and is essential for induction of apotosis both in cellulo and in zebrafish. Our results identify an evolutionary conserved mechanism regulating DNA damage-induced apoptosis.
Item Description:Gesehen am 26.11.2020
Physical Description:Online Resource
ISSN:1091-6490
DOI:10.1073/pnas.1310001110

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