Phosphoregulation of interleukin-1 receptor-associated kinase 1 in inflammatory signaling.

Interleukin-1 receptor-associated kinase 1 (IRAK1) is a serine/threonine kinase that functions as a central transducer of Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling, linking pathogen recognition to the activation of nuclear factor kappa B (NF-κB), mitogen-activated protein kinases (MAPK), and interferon regulatory factors (IRFs). Although the role of IRAK1 in innate immune signaling is well established, its regulatory complexity remains incompletely characterized, particularly regarding the dynamic phosphorylation landscape that governs activation, substrate specificity, and signal termination. This review presents a systematic phosphoproteomics map of IRAK1 phosphorylation, integrating 213 profiling and 33 differential mass spectrometry-based phosphoproteomic datasets from 56 studies. Eighteen phosphosites were identified in the profiling datasets and 16 in the differential datasets across independent expression and acquisition conditions. Among these, Ser131 (detected in 128 profiling and 26 differential datasets) and Ser110 (detected in 26 profiling and nine differential datasets) were the most frequently observed sites. Most high-frequency phosphosites are located within the serine/threonine kinase domain and the C-terminal proline/serine/threonine-rich (ProST) regulatory region of the protein. However, frequent detection does not necessarily indicate functional significance, and these sites are potential candidates for targeted validation. In addition to canonical phosphorylation, this review evaluates the coordinated interplay among phosphorylation, K63/K48-linked ubiquitination, and SUMOylation, which together determine whether signaling is propagated or terminated. We also discuss the non-canonical functions of IRAK1 in transcriptional regulation, antiviral defense, cytoskeletal organization, and oncogenic signaling, and evaluate current pharmacological inhibitors of IRAK1, including Pacritinib, JH-X-119-01, 1, 4-naphthoquinone, and rosoxacin. Overall, this review provides a systematic, data-informed framework for prioritizing phosphosite-specific functional studies to identify phospho-dependent interaction interfaces as potential targets for precision clinical interventions and biomarker development in inflammatory diseases and cancer.