BLK positively regulates TLR/IL-1R signaling by catalyzing TOLLIP phosphorylation

文献类型： 外文期刊

第一作者： Li, Wei-Wei

作者： Li, Wei-Wei;Fan, Xu-Xu;Zhu, Zi-Xiang;Zhu, Zhao-Yu;Cao, Xue-Jing;Pei, Dan-Shi;Wang, Yi-Zhuo;Zhang, Ji-Yan;Zheng, Hai-Xue;Li, Wei-Wei;Xu, Zhi-Sheng;Wang, Yan-Yi;Li, Wei-Wei;Fan, Xu-Xu;Zhu, Zi-Xiang;Zhu, Zhao-Yu;Cao, Xue-Jing;Pei, Dan-Shi;Wang, Yi-Zhuo;Zhang, Ji-Yan;Zheng, Hai-Xue

作者机构：

期刊名称：JOURNAL OF CELL BIOLOGY （ 影响因子：7.8； 五年影响因子：8.8 ）

ISSN： 0021-9525

年卷期： 2023 年 223 卷 2 期

页码：

收录情况： SCI

摘要： Li et al. demonstrate that activated BLK phosphorylates TOLLIP and promotes its dissociation from IRAK1 to enable efficient inflammatory response. This study uncovers uncharacterized roles of BLK in regulating TLR/IL-1R-mediated inflammatory responses and suggests the possibility of targeting this kinase for alleviation of excessive inflammation. 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-1 beta challenge. Mechanistically, BLK is preassociated with IL1R1 and IL1RAcP in resting cells. IL-1 beta 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.

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