TBK1-Zyxin Signaling Controls Tumor-associated Macrophage Recruitment to Mitigate Antitumor Immunity

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2024 Sep 20

PMID 39304793

Authors

Ruyuan Zhou

Mengqiu Wang

Xiao Li

Yutong Liu

Yihan Yao

Ailian Wang

Chen Chen

Qian Zhang

Qirou Wu

Qi Zhang

Dante Neculai

Bing Xia

Jian-Zhong Shao

Xin-Hua Feng

Tingbo Liang

Jian Zou

Xiaojian Wang

Pinglong Xu

Affiliations

Soon will be listed here.

Abstract

Mechanical control is fundamental for cellular localization within a tissue, including for tumor-associated macrophages (TAMs). While the innate immune sensing pathways cGAS-STING and RLR-MAVS impact the pathogenesis and therapeutics of malignant diseases, their effects on cell residency and motility remain incompletely understood. Here, we uncovered that TBK1 kinase, activated by cGAS-STING or RLR-MAVS signaling in macrophages, directly phosphorylates and mobilizes Zyxin, a key regulator of actin dynamics. Under pathological conditions and in STING or MAVS signalosomes, TBK1-mediated Zyxin phosphorylation at S143 facilitates rapid recruitment of phospho-Zyxin to focal adhesions, leading to subsequent F-actin reorganization and reduced macrophage migration. Intratumoral STING-TBK1-Zyxin signaling was evident in TAMs and critical in antitumor immunity. Furthermore, myeloid-specific or global disruption of this signaling decreased the population of CD11b F4/80 TAMs and promoted PD-1-mediated antitumor immunotherapy. Thus, our findings identify a new biological function of innate immune sensing pathways by regulating macrophage tissue localization, thus providing insights into context-dependent mitigation of antitumor immunity.

References

Sliter D, Martinez J, Hao L, Chen X, Sun N, Fischer T . Parkin and PINK1 mitigate STING-induced inflammation. Nature. 2018; 561(7722):258-262. PMC: 7362342. DOI: 10.1038/s41586-018-0448-9. View

Kwon J, Bakhoum S . The Cytosolic DNA-Sensing cGAS-STING Pathway in Cancer. Cancer Discov. 2019; 10(1):26-39. PMC: 7151642. DOI: 10.1158/2159-8290.CD-19-0761. View

Grange J, Moody J, Ascione M, Hansen M . Zyxin-VASP interactions alter actin regulatory activity in zyxin-VASP complexes. Cell Mol Biol Lett. 2012; 18(1):1-10. PMC: 6275665. DOI: 10.2478/s11658-012-0035-2. View

Wynn T, Vannella K . Macrophages in Tissue Repair, Regeneration, and Fibrosis. Immunity. 2016; 44(3):450-462. PMC: 4794754. DOI: 10.1016/j.immuni.2016.02.015. View

Kang X, Deng Y, Cao Y, Huo Y, Luo J . Zyxin Mediates Vascular Repair Endothelial Migration Promoted by Forskolin in Mice. Front Physiol. 2021; 12:741699. PMC: 8531502. DOI: 10.3389/fphys.2021.741699. View

Wang A, Chen C, Mei C, Liu S, Xiang C, Fang W . Innate immune sensing of lysosomal dysfunction drives multiple lysosomal storage disorders. Nat Cell Biol. 2024; 26(2):219-234. DOI: 10.1038/s41556-023-01339-x. View

Fu J, Kanne D, Leong M, Glickman L, McWhirter S, Lemmens E . STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade. Sci Transl Med. 2015; 7(283):283ra52. PMC: 4504692. DOI: 10.1126/scitranslmed.aaa4306. View

Roers A, Hiller B, Hornung V . Recognition of Endogenous Nucleic Acids by the Innate Immune System. Immunity. 2016; 44(4):739-54. DOI: 10.1016/j.immuni.2016.04.002. View

Corrales L, Glickman L, McWhirter S, Kanne D, Sivick K, Katibah G . Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity. Cell Rep. 2015; 11(7):1018-30. PMC: 4440852. DOI: 10.1016/j.celrep.2015.04.031. View

10.

Luo W, Wang Y, Zhang L, Ren P, Zhang C, Li Y . Critical Role of Cytosolic DNA and Its Sensing Adaptor STING in Aortic Degeneration, Dissection, and Rupture. Circulation. 2019; 141(1):42-66. PMC: 6939474. DOI: 10.1161/CIRCULATIONAHA.119.041460. View

11.

Xiao Y, Zou Q, Xie X, Liu T, Li H, Jie Z . The kinase TBK1 functions in dendritic cells to regulate T cell homeostasis, autoimmunity, and antitumor immunity. J Exp Med. 2017; 214(5):1493-1507. PMC: 5413337. DOI: 10.1084/jem.20161524. View

12.

Gao D, Li T, Li X, Chen X, Li Q, Wight-Carter M . Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases. Proc Natl Acad Sci U S A. 2015; 112(42):E5699-705. PMC: 4620884. DOI: 10.1073/pnas.1516465112. View

13.

Chan C, Liu X, Tang X, Fu H, Ye K . Akt phosphorylation of zyxin mediates its interaction with acinus-S and prevents acinus-triggered chromatin condensation. Cell Death Differ. 2007; 14(9):1688-99. DOI: 10.1038/sj.cdd.4402179. View

14.

Marcus A, Mao A, Lensink-Vasan M, Wang L, Vance R, Raulet D . Tumor-Derived cGAMP Triggers a STING-Mediated Interferon Response in Non-tumor Cells to Activate the NK Cell Response. Immunity. 2018; 49(4):754-763.e4. PMC: 6488306. DOI: 10.1016/j.immuni.2018.09.016. View

15.

Sun Y, Revach O, Anderson S, Kessler E, Wolfe C, Jenney A . Targeting TBK1 to overcome resistance to cancer immunotherapy. Nature. 2023; 615(7950):158-167. PMC: 10171827. DOI: 10.1038/s41586-023-05704-6. View

16.

Davies L, Jenkins S, Allen J, Taylor P . Tissue-resident macrophages. Nat Immunol. 2013; 14(10):986-95. PMC: 4045180. DOI: 10.1038/ni.2705. View

17.

Yu C, Davidson S, Harapas C, Hilton J, Mlodzianoski M, Laohamonthonkul P . TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS. Cell. 2020; 183(3):636-649.e18. PMC: 7599077. DOI: 10.1016/j.cell.2020.09.020. View

18.

Samson N, Ablasser A . The cGAS-STING pathway and cancer. Nat Cancer. 2022; 3(12):1452-1463. DOI: 10.1038/s43018-022-00468-w. View

19.

Chen S, Liu S, Wang J, Wu Q, Wang A, Guan H . TBK1-Mediated DRP1 Targeting Confers Nucleic Acid Sensing to Reprogram Mitochondrial Dynamics and Physiology. Mol Cell. 2020; 80(5):810-827.e7. DOI: 10.1016/j.molcel.2020.10.018. View

20.

King K, Aguirre A, Ye Y, Sun Y, Roh J, Ng Jr R . IRF3 and type I interferons fuel a fatal response to myocardial infarction. Nat Med. 2017; 23(12):1481-1487. PMC: 6477926. DOI: 10.1038/nm.4428. View