Abstract：
The translocation of stimulator of interferon genes (STING) from the endoplasmic reticulum (ER) to the ER-Golgi intermediate compartment (ERGIC) enables its activation. However, the mechanism underlying the regulation of STING exit from the ER remains elusive. Here, we found that STING induces the activation of transforming growth factor beta-activated kinase 1 (TAK1) prior to STING trafficking in a TAK1 binding protein 1 (TAB1)-dependent manner. Intriguingly, activated TAK1 directly mediates STING phosphorylation on serine 355, which facilitates its interaction with STING ER exit protein (STEEP) and thereby promotes its oligomerization and translocation to the ERGIC for subsequent activation. Importantly, activation of TAK1 by monophosphoryl lipid A, a TLR4 agonist, boosts cGAMP-induced antitumor immunity dependent on STING phosphorylation in a mouse allograft tumor model. Taken together, TAK1 was identified as a checkpoint for STING activation by promoting its trafficking, providing a basis for combinatory tumor immunotherapy and intervention in STING-related diseases.
摘要：
干扰素基因（STING）的刺激物从内质网（ER）到ER-高尔基体中间区室（ERGIC）的易位使其活化。然而,STING退出急诊室的调节机制仍然难以捉摸。这里,我们发现STING以TAK1结合蛋白1（TAB1）依赖性方式在STING运输之前诱导转化生长因子β激活激酶1（TAK1）的激活。有趣的是，激活的TAK1直接介导丝氨酸355上的STING磷酸化，从而促进其与STINGER退出蛋白（STEEP）的相互作用，从而促进其低聚和易位到ERGIC进行后续激活。重要的是,通过单磷酰脂质A激活TAK1，TLR4激动剂，在小鼠同种异体移植肿瘤模型中，cGAMP诱导的抗肿瘤免疫依赖于STING磷酸化。一起来看,TAK1通过促进其贩运被确定为STING激活的检查站，为肿瘤联合免疫治疗和干预STING相关疾病提供依据。
