TRAF6 possesses an E3 ubiquitin ligase activity that catalyzes K63‐linked autoubiquitination and/or the synthesis of free K63‐linked polyubiquitin chains.
MyD88 subsequently recruits several kinases, including IL‐1 receptor‐associated kinase 1 (IRAK1), IRAK2, and IRAK4, as well as E3 ubiquitin ligase tumor necrosis factor receptor‐associated factor 6 (TRAF6) to form a protein complex termed Myddosome 5, 6, 7. Upon ligand binding, all TLRs except TLR3 and IL‐1R recruit the same adaptor protein myeloid differentiation factor 88 (MyD88) to the receptors 4, 5. TLRs and IL‐1R share a common toll/interleukin‐1 receptor (TIR) domain in their intracellular region 1. IL‐1β binds to the IL‐1 receptor (IL‐1R) to initiate signal transduction. It is critical for both local and systemic inflammation and contributes to both innate and adaptive immune responses 3. IL‐1β is an important pro‐inflammatory cytokine which could be induced by PRR‐mediated signaling. Members of TLRs recognize various microbial components such as nucleic acids, lipids, proteins, lipoproteins, and glycoproteins, leading to the activation of innate immune response as well as production of pro‐inflammatory cytokines 1, 2. The innate immune system senses invading pathogens by germline‐encoded pattern recognition receptors (PRRs) which recognize specific molecular patterns of pathogens. Our findings suggest that RNF152‐mediated oligomerization of MyD88 is important for TLR/ IL‐1R‐mediated inflammatory response. Mechanistically, RNF152 interacts with the adaptor protein MyD88 and enhances oligomerization of MyD88, which is essential for the recruitment of downstream signaling components and activation of TLR/ IL‐1R‐mediated signal transduction. RNF152‐deficient mice produce less inflammatory cytokines in response to LPS and are more resistant to LPS‐induced lethal endotoxemia. Overexpression of RNF152 potentiates IL‐1β‐ and LPS‐induced NF‐κB activation in an ubiquitination‐independent manner, whereas knockdown of RNF152 has the opposite effects. In this study, we identify the E3 ubiquitin ligase RNF152 as a positive regulator of TLR/ IL‐1R‐mediated signaling. TLRs and interleukin‐1 receptor ( IL‐1R) share similar cytosolic domains and signaling processes. IL‐1β is an important pro‐inflammatory cytokine that also plays pivotal roles in shaping the adaptive immune response. Toll‐like receptors ( TLRs) are important pattern recognition receptors ( PRRs) that are critical for the defense against invading pathogens.