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A Non-Canonical IRAK Signaling Pathway Triggered by DNA Damage

Authors :
Yuanyuan Li
Richa B. Shah
Samanta Sarti
Alicia L. Belcher
Brian J. Lee
Andrej Gorbatenko
Francesca Nemati
Ian Yu
Zoe Stanley
Zhengping Shao
Jose M. Silva
Shan Zha
Samuel Sidi
Source :
bioRxiv
Publication Year :
2023
Publisher :
Cold Spring Harbor Laboratory, 2023.

Abstract

Interleukin-1 receptor (IL-1R)-associated kinases (IRAKs) are core effectors of Toll-like receptor (TLR) and IL-1R signaling, with no reported roles outside of innate immunity. We find that vertebrate cells exposed to ionizing radiation (IR) sequentially activate IRAK4 and IRAK1 through a phosphorylation cascade mirroring that induced by TLR/IL-1R, resulting in a potent anti-apoptotic response. However, IR-induced IRAK1 activation does not require the receptors or the IRAK4/1 adaptor protein MyD88, and instead of remaining in the cytoplasm, the activated kinase is immediately transported to the nucleus via a conserved nuclear localization signal. We identify: double-strand DNA breaks (DSBs) as the biologic trigger for this pathway; the E3 ubiquitin ligase Pellino1 as the scaffold enabling IRAK4/1 activation in place of TLR/IL-1R-MyD88; and the pro-apoptotic PIDDosome (PIDD1-RAIDD-caspase-2) as a critical downstream target in the nucleus. The data delineate a non-canonical IRAK signaling pathway derived from, or ancestral to, TLR signaling. This DSB detection pathway, which is also activated by genotoxic chemotherapies, provides multiple actionable targets for overcoming tumor resistance to mainstay cancer treatments.

Subjects

Subjects :
Article

Details

Database :
OpenAIRE
Journal :
bioRxiv
Accession number :
edsair.doi.dedup.....145271a44514f51d38e0476c189df026
Full Text :
https://doi.org/10.1101/2023.02.08.527716