A noncanonical IRAK4-IRAK1 pathway counters DNA damage–induced apoptosis independently of TLR/IL-1R signaling

Interleukin-1 receptor (IL-1R)–associated kinases (IRAKs) are core effectors of Toll-like receptors (TLRs) and IL-1R in innate immunity. Here, we found that IRAK4 and IRAK1 together inhibited DNA damage–induced cell death independently of TLR or IL-1R signaling. In human cancer cells, IRAK4 was activated downstream of ATR kinase in response to double-strand breaks (DSBs) induced by ionizing radiation (IR). Activated IRAK4 then formed a complex with and activated IRAK1. The formation of this complex required the E3 ubiquitin ligase Pellino1, acting structurally but not catalytically, and the activation of IRAK1 occurred independently of extracellular signaling, intracellular TLRs, and the TLR/IL-1R signaling adaptor MyD88. Activated IRAK1 translocated to the nucleus in a Pellino2-dependent manner. In the nucleus, IRAK1 bound to the PIDD1 subunit of the proapoptotic PIDDosome and interfered with platform assembly, thus supporting cell survival. This noncanonical IRAK signaling pathway was also activated in response to other DSB-inducing agents. The loss of IRAK4, of IRAK4 kinase activity, of either Pellino protein, or of the nuclear localization sequence in IRAK1 sensitized p53-mutant zebrafish to radiation. Thus, the findings may lead to strategies for overcoming tumor resistance to conventional cancer treatments. Separate to their role in innate immunity, IRAK kinases mediate resistance to DNA-damaging agents. Editor’s summary The kinase IRAK1 supports radiotherapy resistance in cancers. Li et al. found that this function of IRAK1 was independent of its regulation by innate immune receptor signaling. Double-stranded DNA breaks induced by radiation triggered IRAK4-dependent activation and nuclear translocation of IRAK1, which bound to and inhibited a proapoptotic complex, thereby supporting cell survival. This mechanism required the DNA damage response kinase ATR and Pellino family ubiquitin ligases. Disrupting the pathway sensitized p53-mutant zebrafish to radiation, providing potential targets for overcoming radiation resistance in some cancers. —Leslie K. Ferrarelli

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