# A Non-Canonical IRAK1 Signaling Pathway Triggered by Ionizing Radiation

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $358,280

## Abstract

Project Summary
 IRAK1 is a core transducer of Toll-like receptor (TLR) and IL-1R-mediated innate immune signaling
from flies to humans. In response to pathogen infection, ligated TLR/IL-1Rs activate IRAK1 via formation of the
MyDDosome complex (IL-1R/TLR—MyD88-IRAK4-IRAK1) at the cell surface. Once phosphorylated by IRAK4,
activated IRAK1 is released into the cytoplasm where it engages TRAF6-NF-kB and other proinflammatory
cascades. Until recently, IRAK1 had not been implicated in processes other than the microbial response.
 In an unbiased zebrafish screen, we recently identified IRAK1 as essential for cell survival in response to
ionizing radiation (IR) (Liu et al., Nat Cell Biol 2019). This function is conserved in human cells and drives
cellular resistance to radiotherapy in tumor models. Surprisingly, while IR-induced IRAK1 activation requires
IRAK4 within a MyDDosome-like platform, the pathway does not involve IL-1R, TLRs or MyD88. Furthermore,
rather than remaining in the cytoplasm to engage TRAF6, IR-activated IRAK1 is immediately translocated to
the nucleus (Li, et al., Sci Signal in press). Once in the nucleus, a fraction of IRAK1 travels to the nucleolus
where its antagonistic target, the PIDDosome, resides (Ando et al., J Cell Biol 2017; Shah et al., Dev Cell
2021). IR-induced IRAK signaling thus diverges from TLR signaling both upstream and downstream of the
IRAK4-IRAK1 core module, revealing the existence of a non-canonical IRAK signaling (NCIS) pathway.
 With the NCIS pathway backbone in hand, we will now uncover the underlying signal transduction. In Aim
1, we will define the process through which DNA breaks in the nucleus trigger IRAK4-IRAK1 platform formation
in the cytoplasm. Our preliminary data identify cGAS, a DNA sensor which shuttles in and out of the nucleus,
as a strong candidate for initiating NCIS in response to DNA damage-induced ATR signlaling. In Aim 2, we will
first identify the adaptor molecule responsible for nucleating the IRAK4/1 activation platform in place of MyD88,
with the IRAK-interacting protein Pellino1 and death domain-containing protein kinase DAPK1 as lead
candidates (Aim 2A). We will also define the mechanism by which the sister E3 ubiquitin ligase, Pellino2,
orchestrates the nuclear translocation of activated IRAK1 (Aim 2B). Finally, we will elucidate the biologic role of
NCIS; we will integrate our zebrafish and mammalian studies with Drosophila models to ask if NCIS is
conserved in flies, and whether it evolved as a mechanism guarding against unwarranted apoptosis caused by
UV light or the endogenously generated DSBs necessary for meiotic and VDJ recombination (Aim 2C).
 These studies will illuminate a novel stress response pathway in animals and identify a biologic role for
IRAK kinases outside of innate immunity. Because NCIS has been implicated as a pervasive driver of tumor
resistance to radiation therapy (R-RT), an additional immediate impact of our work might be the discovery of
diagnostic ...

## Key facts

- **NIH application ID:** 10981158
- **Project number:** 2R01GM135301-05A1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Samuel Sidi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $358,280
- **Award type:** 2
- **Project period:** 2019-09-15 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981158

## Citation

> US National Institutes of Health, RePORTER application 10981158, A Non-Canonical IRAK1 Signaling Pathway Triggered by Ionizing Radiation (2R01GM135301-05A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10981158. Licensed CC0.

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