The multifunctional adaptor protein HIP-55 couples Smad7 to accelerate TGF-β type I receptor degradation
The multifunctional adaptor protein HIP-55 couples Smad7 to accelerate TGF-β type I receptor degradation
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多功能接头蛋白HIP-55偶联Smad7加速TGF-β I型受体降解
DOI：
10.1038/s41401-021-00741-1
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发表时间：
2021-07-30
影响因子：
8.2
通讯作者：
Li, Zi-jian
中科院分区：
文献类型：
--
作者：
Sun, Yang;Li, Zi-jian
转化生长因子（tgf - β）是一种多功能多肽，在调节多种细胞功能和生理过程中发挥重要作用。tgf - β信号传导功能障碍导致许多疾病，如心血管疾病、癌症和免疫疾病。负反馈调节的稳态对信号的鲁棒性、持续时间和特异性至关重要，从而精确控制生理和病理生理过程。然而，tgf - β信号负调控的整合和协调的潜在机制尚不清楚。在这里，我们发现造血祖细胞激酶相互作用蛋白55kda （HIP-55）在tgf - β刺激下上调，而HIP-55的缺失导致tgf - β信号过度激活和下游细胞外基质（ECM）基因的异常积累。HIP-55与Smad7相互作用，并与Smad7/Axin复合物形成竞争，抑制Axin介导的Smad7降解。HIP-55进一步将Smad7与T β RI结合，而不是与T β RI结合，从而驱动T β RI降解。总之，我们的研究结果证明了HIP-55的效应和负反馈功能耦合的新机制，并可能为治疗tgf - β信号相关的人类疾病提供新的策略。
Transforming growth factor beta (TGF-beta) is a multifunctional polypeptide that plays critical roles in regulating a broad range of cellular functions and physiological processes. TGF-beta signalling dysfunction contributes to many disorders, such as cardiovascular diseases, cancer and immunological diseases. The homoeostasis of negative feedback regulation is critical for signal robustness, duration and specificity, which precisely control physiological and pathophysiological processes. However, the underlying mechanism by which the negative regulation of TGF-beta signalling is integrated and coordinated is still unclear. Here, we reveal that haematopoietic progenitor kinase-interacting protein of 55 kDa (HIP-55) was upregulated upon TGF-beta stimulation, while the loss of HIP-55 caused TGF-beta signalling overactivation and the abnormal accumulation of downstream extracellular matrix (ECM) genes. HIP-55 interacts with Smad7 and competes with Smad7/Axin complex formation to inhibit the Axin-mediated degradation of Smad7. HIP-55 further couples Smad7 to T beta RI but not T beta RII, driving T beta RI degradation. Altogether, our findings demonstrate a new mechanism by which the effector and negative feedback functions of HIP-55 are coupled and may provide novel strategies for the treatment of TGF-beta signalling-related human diseases.