State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.
Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences , Wuhan, China.
J Cell Biol. 2024 Feb 5;223(2). doi: 10.1083/jcb.202302081. Epub 2023 Dec 11.
TLR/IL-1R signaling plays a critical role in sensing various harmful foreign pathogens and mounting efficient innate and adaptive immune responses, and it is tightly controlled by intracellular regulators at multiple levels. In particular, TOLLIP forms a constitutive complex with IRAK1 and sequesters it in the cytosol to maintain the kinase in an inactive conformation under unstimulated conditions. However, the underlying mechanisms by which IRAK1 dissociates from TOLLIP to activate TLR/IL-1R signaling remain obscure. Herein, we show that BLK positively regulates TLR/IL-1R-mediated inflammatory response. BLK-deficient mice produce less inflammatory cytokines and are more resistant to death upon IL-1β challenge. Mechanistically, BLK is preassociated with IL1R1 and IL1RAcP in resting cells. IL-1β stimulation induces heterodimerization of IL1R1 and IL1RAcP, which further triggers BLK autophosphorylation at Y309. Activated BLK directly phosphorylates TOLLIP at Y76/86/152 and further promotes TOLLIP dissociation from IRAK1, thereby facilitating TLR/IL-1R-mediated signal transduction. Overall, these findings highlight the importance of BLK as an active regulatory component in TLR/IL-1R signaling.
TLR/IL-1R 信号通路在识别各种有害的外源病原体并引发有效的固有和适应性免疫反应方面发挥着关键作用，它受到多个层面的细胞内调节剂的严格控制。特别是，TOLLIP 与 IRAK1 形成一个组成性复合物，并将其隔离在细胞质中，以使激酶在未受刺激的条件下保持无活性构象。然而，IRAK1 从 TOLLIP 上解离以激活 TLR/IL-1R 信号通路的潜在机制仍不清楚。在此，我们表明 BLK 正向调节 TLR/IL-1R 介导的炎症反应。BLK 缺陷型小鼠产生的炎症细胞因子较少，在受到 IL-1β 挑战时更能抵抗死亡。在机制上，BLK 在静止细胞中与 IL1R1 和 IL1RAcP 预先结合。IL-1β 刺激诱导 IL1R1 和 IL1RAcP 的异二聚化，进而触发 BLK 在 Y309 处的自身磷酸化。激活的 BLK 直接在 Y76/86/152 处磷酸化 TOLLIP，并进一步促进 TOLLIP 与 IRAK1 的解离，从而促进 TLR/IL-1R 介导的信号转导。总的来说，这些发现强调了 BLK 作为 TLR/IL-1R 信号通路中一个积极的调节成分的重要性。
