A Non-Canonical IRAK Signaling Pathway Triggered by DNA Damage

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.

Biology of Pellino1: a potential therapeutic target for inflammation in diseases and cancers

“…This event recruits IRAK1 to Peli1 via IRAK4, leading to IRAK1 activation and nuclear translocation through Thr209 phosphorylation. Nuclear IRAK1 co-localizes with γH2AX and inhibits the pro-apoptotic PIDDosome complex (PIDD1-RAIDD-caspase-2), exerting an anti-apoptotic function ( 46 ).…”

“…DNA double-strand breaks (DSBs) signaling and repair are crucial for maintaining genomic integrity. Peli1 is crucial in DNA damage-responsive protein accumulation and efficient homologous recombination (HR) repair, making it essential for DSB-responsive pathways (Figure 3) (33)(34)(35)46). Peli1 participates in multiple pathways associated with the DNA damage response (35).…”