2. Academic Validation
  3. TAK1 is an essential kinase for STING trafficking

TAK1 is an essential kinase for STING trafficking

  • Mol Cell. 2023 Nov 2;83(21):3885-3903.e5. doi: 10.1016/j.molcel.2023.09.009.
Mingtong Ma 1,  Yifang Dang 2,  Boran Chang 3,  Fei Wang 1,  Junfang Xu 4,  Li Chen 5,  Hang Su 6,  Jinsong Li 7,  Baoxue Ge 8,  Chang Chen 9,  Haipeng Liu 10
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine; Shanghai 200433, China; Department of Microbiology and Immunology, School of Medicine, Tongji University, Shanghai 200072, China.
  • 2 Department of Microbiology and Immunology, School of Medicine, Tongji University, Shanghai 200072, China; Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine; Shanghai 200433, China.
  • 3 State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
  • 4 Clinical Translation Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine; Shanghai 200433, China.
  • 5 Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine; Shanghai 200433, China.
  • 6 Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine; Shanghai 200433, China.
  • 7 State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: jsli@sibcb.ac.cn.
  • 8 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine; Shanghai 200433, China; Department of Microbiology and Immunology, School of Medicine, Tongji University, Shanghai 200072, China; Clinical Translation Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine; Shanghai 200433, China. Electronic address: gebaoxue@sibs.ac.cn.
  • 9 Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine; Shanghai 200433, China. Electronic address: chenthoracic@163.com.
  • 10 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine; Shanghai 200433, China; Department of Microbiology and Immunology, School of Medicine, Tongji University, Shanghai 200072, China; Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine; Shanghai 200433, China. Electronic address: haipengliu@tongji.edu.cn.
PMID: 37832545 DOI: 10.1016/j.molcel.2023.09.009
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.

Keywords

STING ER exit protein; TAK1 binding protein 1; immunotherapy; monophosphoryl lipid A; phosphorylation; stimulator of interferon genes; trafficking; transforming growth factor beta-activated kinase 1.

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