干扰素基因刺激子 (STING) 从内质网 (ER) 易位至 ER-高尔基中间室 (ERGIC) 使其激活。然而，STING 从 ER 退出的调节机制仍然难以捉摸。在这里，我们发现，在 STING 以 TAK1 结合蛋白 1 (TAB1) 依赖性方式运输之前，STING 会诱导转化生长因子 β 激活激酶 1 (TAK1) 的激活。有趣的是，激活的 TAK1 直接介导 STING 丝氨酸 355 上的磷酸化，从而促进其与 STING ER 退出蛋白 (STEEP) 的相互作用，从而促进其寡聚化并易位至 ERGIC 以进行后续激活。重要的是，在小鼠同种异体移植肿瘤模型中，单磷酰脂质 A（一种 TLR4 激动剂）对 TAK1 的激活可增强 cGAMP 诱导的依赖于 STING 磷酸化的抗肿瘤免疫。总而言之，TAK1 通过促进其运输而被确定为 STING 激活的检查点，为组合肿瘤免疫疗法和 STING 相关疾病的干预提供基础。版权所有 © 2023 Elsevier Inc. 保留所有权利。

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.Copyright © 2023 Elsevier Inc. All rights reserved.