TAK1 is an essential kinase for STING trafficking

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 oligomer-ization and translocation to the ERGIC for subsequent activation. Importantly, activation of TAK1 by mono-phosphoryl lipid A, a TLR4 agonist, boosts cGAMP-induced antitumor immunity dependent on STING phos-phorylation 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 interven-tion in STING-related diseases.

Automated summary

In this study, the researchers identified the mechanism underlying the regulation of STING exit from the endoplasmic reticulum. They found that activated TAK1 directly mediates STING phosphorylation, promoting its oligomerization and translocation for subsequent activation. This finding has important implications for tumor immunotherapy and intervention in STING-related diseases.