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TBK1-Zyxin signaling mitigates antitumor immunity by mechanical control of tumor-associated macrophage residency

ABSTRACT: Mechanical control of cell residency, such as tumor-associated macrophages (TAMs), is a fundamental cellular and tissue physiology process. While innate immune sensing pathways such as cGAS-STING signaling and RLR-MAVS signaling impact both the pathogenesis and therapeutics of malignant diseases, their effects on cell residency and motility remain incompletely understood. Here, we uncovered a novel biological function by which TBK1, activated by cGAS-STING or RLR-MAVS signaling, directly phosphorylates and mobilizes Zyxin, a key regulator of actin dynamics. Under pathological conditions, TBK1-mediated Zyxin phosphorylation at the S143 residue in STING or MAVS signalosomes facilitates rapid recruitment of phospho-Zyxin to focal adhesions, a process independent of IRF3 and leads to subsequent F-actin reorganization and macrophage tissue residency. Noticeably, intratumoral STING-TBK1-Zyxin signaling was evidently in TAMs and critical in antitumor immunity, while myeloid-specific or global intervention in this chemomechanical signaling significantly decreased CD11b+F4/80+ TAMs and promoted PD-1-mediated antitumor immunotherapy. Thus, our findings identify a new biological function downstream of TBK1 signaling that grants macrophage residency as a prominent aspect of innate immune sensing and provides unanticipated insights into context-dependent mitigation of antitumor immunity.

ORGANISM(S): Homo sapiens (human) Mus musculus (mouse)

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PROVIDER: S-BSST1517 | biostudies-other |

REPOSITORIES: biostudies-other

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TBK1-Zyxin signaling controls tumor-associated macrophage recruitment to mitigate antitumor immunity

Project description: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.

| S-SCDT-10_1038-S44318-024-00244-9 | biostudies-other

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The kinase TBK1 functions in dendritic cells to regulate T cell homeostasis, autoimmunity, and antitumor immunity.

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The methyltransferase PRMT6 attenuates antiviral innate immunity by blocking TBK1-IRF3 signaling.

Project description:Protein arginine methyltransferases (PRMTs) play diverse biological roles and are specifically involved in immune cell development and inflammation. However, their role in antiviral innate immunity has not been elucidated. Viral infection triggers the TBK1-IRF3 signaling pathway to stimulate the production of type-I interferon, which mediates antiviral immunity. We performed a functional screen of the nine mammalian PRMTs for regulators of IFN-? expression and found that PRMT6 inhibits the antiviral innate immune response. Viral infection also upregulated PRMT6 protein levels. We generated PRMT6-deficient mice and found that they exhibited enhanced antiviral innate immunity. PRMT6 deficiency promoted the TBK1-IRF3 interaction and subsequently enhanced IRF3 activation and type-I interferon production. Mechanistically, viral infection enhanced the binding of PRMT6 to IRF3 and inhibited the interaction between IRF3 and TBK1; this mechanism was independent of PRMT6 methyltransferase activity. Thus, PRMT6 inhibits antiviral innate immunity by sequestering IRF3, thereby blocking TBK1-IRF3 signaling. Our work demonstrates a methyltransferase-independent role for PRMTs. It also identifies a negative regulator of the antiviral immune response, which may protect the host from the damaging effects of an overactive immune system and/or be exploited by viruses to escape immune detection.

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Innate ?? T Cells Mediate Antitumor Immunity by Orchestrating Immunogenic Macrophage Programming.

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STING Activated Tumor-Intrinsic Type I Interferon Signaling Promotes CXCR3 Dependent Antitumor Immunity in Pancreatic Cancer.

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| S-EPMC8081932 | biostudies-literature

Adiponectin receptor signaling on dendritic cells blunts antitumor immunity.

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| S-EPMC4314963 | biostudies-literature

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