Cell Discovery
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2025
·Vol. 11
·期 1
·1-14
·
IF 12.5
Wang Jinrui,Niu Shenghui,Hu Xiao,Li Tianxing,Liu Shengduo,Tu Yingfeng,Shang Zehua,Zhao Lin,Xu Pinglong,Lin Jingwen,Chen Lu,Billadeau Daniel D.,Jia Da
The cGAS-STING pathway mediates the innate immune response to cytosolic DNA, contributing to surveillance against microbial invasion or cellular damage. Once activated, STING recruits TBK1 at the trans-Golgi network (TGN), which in turn phosphorylates IRF3 to induce type I interferon (IFN-I) expression. In contrast to STING, little is known about how TBK1 is transported to the TGN for activation. Here, we show that multiple TGN tethering factors, a group of proteins involved in vesicle capturing, are indispensable for STING-IFN-I signaling. Deletion of TBC1D23, a recently reported tethering factor, in mice impairs the STING-IFN-I signaling, but with insignificant effect on STING-NF-κB signaling. Mechanistically, TBC1D23 interacts with TBK1 via the WASH complex subunit FAM21 and promotes its endosome-to-TGN translocation. Furthermore, multiple TGN tethering factors were reduced in aged mice and senescent fibroblasts. In summary, our study uncovers that TGN tethering factors are key regulators of the STING-IFN-I signaling and suggests that their reduction in senescence may produce aberrant STING signaling.
研究领域:
免疫学
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细胞生物学
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分子生物学
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Cell Reports
·
2025
·
IF 6.9
Li Chai,Chaoqun Li,Xuefeng Wang,Yanyang Qin,Hemin Sun,Jie Du,Liu Yang,Dongmei Hu,Jianan Xiong,Zhiyuan Zhao,Rong Gong,Tao Wu,Meng Wu,Meng Nie,Jialin Gao,Jihui Jia,Chengjiang Gao,Wei Zhao,Huan Zhou,Dongwei Kang,Mutian Jia
Perturbation of energy metabolism is an essential feature during infection and inflammation. TANK-binding kinase 1 (TBK1) is crucial for initiating the innate immune response against viral infection, although aberrant and ongoing TBK1 activation induces excessive production of type I interferons (IFN-I). Nonetheless, the mechanisms whereby energy metabolism controls TBK1 activation remain unclear. Here, we elucidate a mechanism linking energy metabolism to the inhibition of TBK1-induced IFN-I responses via the immune response gene 1 (IRG1)-itaconic acid axis. Mechanistically, itaconic acid and its derivatives alkylated TBK1 at Cys605, thereby disrupting TBK1 dimerization and rapid activation. IRG1, the enzyme that catalyzes itaconic acid production, is upregulated during late-phase viral infection and acts as a feedback regulator to restrain TBK1 activity. We developed itaconic acid-based compounds ITA-5/ITA-9 as alternative TBK1 inhibitors. ITA-5/ITA-9 effectively limited excess IFN-I-mediated hyperinflammation. These findings provide a promising therapeutic strategy for treating diseases mediated by aberrant TBK1 activation.
研究领域:
免疫学
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分子生物学
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代谢调控
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先天免疫
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病毒感染
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信号转导
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药物开发
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FISH & SHELLFISH IMMUNOLOGY
·
2024
·
IF 4.1
Yanwei Zhang,Jing Cen,Haixia Wu,Wa Gao,Zhiying Jia,Mikolaj Adamek,Jun Zou
HnRNP A/B belongs to the heterogeneous nuclear ribonucleoprotein (hnRNP) family and plays an important role in regulating viral protein translation and genome replication. Here, we found that overexpression of hnRNP A/B promoted Spring viremia of carp virus (SVCV) and Cyprinid herpesvirus 3 (CyHV3) replication. Further, hnRNP A/B was shown to act as a negative regulator of type I interferon (IFN) response. Mechanistically, hnRNP A/B interacted with MITA, TBK1 and IRF3 to initiate their degradation. In addition, hnRNP A/B bound to the kinase domain of TBK1, the C terminal domain of MITA and IAD domain of IRF3, and the RRM1 domain of hnRNP A/B bound to TBK1, RRM2 domain bound to IRF3 and MITA. Our study provides novel insights into the functions of hnRNP A/B in regulating host antiviral response.
研究领域:
分子生物学
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病毒学
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免疫学
·
鱼类病理学
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Nature Microbiology
·
2025
·
IF 19.4
Jin Shouheng,He Xing,Wang Zheyu,Zhou Tao,Wang Jun,Pan Guihong,Zhang Yin,Ma Ling,Yang Shuai,Wang Liqiu,Wu Yaoxing,Zou Yilin,Qi Nan,Cui Jun
Metabolic pathways determine cellular fate and function; however, the exact roles of metabolites in host defence against influenza virus remain undefined. Here we employed pharmacological inhibition and metabolomics analysis to show that the metabolic pathways of oxaloacetate (OAA) are integrated with antiviral responses to influenza virus. Cytosolic malate dehydrogenase 1 senses intracellular OAA to undergo dimerization and functions as a scaffold to recruit the transcription factor ETS2 for phosphorylation by the kinase TAOK1 at serine 313. The phosphorylated ETS2 translocates into the nucleus and supports optimal expression of TBK1, an indispensable activator of type I interferon responses. OAA supplementation provides a broad-spectrum antiviral ability, and OAA deficiency caused by Acly genetic ablation decreases antiviral immunity and renders mice more susceptible to lethal H1N1 virus infection. Our results uncover a signalling pathway through cellular OAA sensing that links metabolism and innate immunity to coordinate defence against viral challenge.
研究领域:
免疫学
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病毒学
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代谢生物学
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分子生物学
·
信号转导
·
感染与免疫
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2023
·
IF 5.6
Weixin Li,Zhuqi Huang,Yue Luo,Yaqian Cui,Mingjiang Xu,Wu Luo,Gaojun Wu,Guang Liang
Atherosclerosis (AS) is a chronic inflammatory disease. Recent studies have showed that stimulator of interferon genes (STING), an important protein in innate immunity, mediates pro-inflammatory activation of macrophages in the development of AS. Tetrandrine (TET) is a natural bisbenzylisoquinoline alkaloid isolated from Stepania tetrandra and possesses anti-inflammatory activities, with unknown effects and mechanisms in AS. In this study, we explored the anti-atherosclerotic effects of TET and investigated the underlying mechanisms. Mouse primary peritoneal macrophages (MPMs) are challenged with cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) or oxidized LDL (oxLDL). We found that pretreatment with TET dose-dependently inhibited cGAMP- or oxLDL-induced STING/ TANK-binding kinase 1 (TBK1) signaling, then suppressing nuclear factor kappa-B (NF-κB) activation and pro-inflammatory factor expression in MPMs. ApoE -/- mice were fed a high-fat diet (HFD) to develop an atherosclerotic phenotype. Administration of TET at 20 mg/kg/day significantly reduced HFD-induced atherosclerotic plaques, accompanied with decreased macrophage infiltration, inflammatory cytokine production, fibrosis, and STING/TBK1 activation in aortic plaque lesions. In summary, we demonstrate that TET inhibits STING/TBK1/NF-κB signaling pathway to reduce inflammation in oxLDL-challenged macrophages and alleviate atherosclerosis in HFD-fed ApoE -/- mice. These findings proved that TET could be a potential therapeutic candidate for the treatment of atherosclerosis-related diseases.
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MOLECULAR CELL
·
2026
·Vol. 86
·期 4
·722-739
·
IF 16
Jie Du,Chaoqun Li,Li Chai,Fabao Zhao,Lin Lv,Zongcheng Yang,Zhiyuan Zhao,Rong Gong,Liu Yang,Meng Wu,Meng Nie,Jihui Jia,Dongwei Kang,Chengjiang Gao,Wei Zhao,Mutian Jia
Competition between the host and invading viruses for cellular nutrients determines the outcomes of infectious diseases. Nutrients are increasingly being recognized as regulators that interact with immunological signals, but how immune cells sense specific nutrients to regulate antiviral innate immune responses remains elusive. Here, we establish asparagine (Asn) as an intercellular nutritional checkpoint that is sensed by TANK-binding kinase 1 (TBK1) to drive innate immune responses in human and murine cells. Mechanistically, Asn directly binds to TBK1, which robustly induces TBK1 phase separation and forms liquid-like droplets, promoting TBK1 transautophosphorylation and activation. Moreover, viral infection reduces asparagine synthetase (ASNS) expression to establish an Asn-restricted microenvironment, thereby evading TBK1-triggered host immune defenses. Overall, our results suggest that TBK1 is a natural Asn sensor that links host nutritional homeostasis to antiviral immune responses and reveal that targeting Asn availability is a promising therapeutic strategy for diseases involving dysregulated TBK1 activation.
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Cellular and Molecular Gastroenterology and Hepatology
·
2022
·
IF 8.797
Xin Liu,Wu Luo,Jiahao Chen,Chenghong Hu,Rumbidzai N. Mutsinze,Xu Wang,Yanmei Zhang,Lijiang Huang,Wei Zuo,Guang Liang,Yi Wang
Background & Aims Severe acute pancreatitis can easily lead to systemic inflammatory response syndrome and death. Macrophages are known to be involved in the pathophysiology of acute pancreatitis (AP), and macrophage activation correlates with disease severity. In this study, we examined the role of ubiquitin-specific protease 25, a deubiquitinating enzyme and known regulator of macrophages, in the pathogenesis of AP. Methods We used L-arginine, cerulein, and choline-deficient ethionine-supplemented diet–induced models of AP in Usp25 -/- mice and wild-type mice. We also generated bone marrow Usp25 -/- chimeric mice and initiated L-arginine–mediated AP. Primary acinar cells and bone marrow–derived macrophages were isolated from wild-type and Usp25 -/- mice to dissect molecular mechanisms. Results Our results show that Usp25 deficiency exacerbates pancreatic and lung injury, neutrophil and macrophage infiltration, and systemic inflammatory responses in L-arginine, cerulein, and choline-deficient ethionine-supplemented diet–induced models of AP. Bone marrow Usp25 -/- chimeric mice challenged with L-arginine show that Usp25 deficiency in macrophages exaggerates AP by up-regulating the TANK-binding kinase 1 (TBK1)–nuclear factor-κB (NF-κB) signaling pathway. Similarly, in vitro data confirm that Usp25 deficiency enhances the TBK1–NF-κB pathway, leading to increased expression of inflammatory cytokines in bone marrow–derived macrophages. Conclusions Usp25 deficiency in macrophages enhances TBK1–NF-κB signaling, and the induction of inflammatory chemokines and type I interferon-related genes exacerbates pancreatic and lung injury in AP.
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Communications Biology
·
2022
·Vol. 5
·期 1
·1-18
·
IF 6.548
Wang Man,Xu Rong,Liu Xiaoli,Zhang Ling,Qiu Siyan,Lu Yuting,Zhang Peng,Yan Ming,Zhu Jing
Berberine (BBR) exerts specific therapeutic effects on various diseases such as diabetes, obesity, and other inflammation-associated diseases. However, the low oral bioavailability (below 1%) of berberine due to its poor solubility and membrane permeability limits its clinical use. In this paper, we have prepared a 1:1 co-crystal berberine-ibuprofen (BJ) using drug salt metathesis and co-crystal technology. Pharmacokinetic studies demonstrate a 3-fold increase in vivo bioavailability of BJ compared to that of BBR, and BJ is more effective in treating obesity and its related metabolism in vitro and in vivo. We also find that BJ promotes mitochondrial biogenesis by inhibiting TBK1 and inducing AMP‐activated protein kinase (AMPK) phosphorylation, and BJ increases adipocyte sensitivity to catecholamine by inhibiting IKKε. Together, our findings support that co-crystal BJ is likely to be an effective agent for treating obesity and its related metabolic diseases targeting TBK1 and IKKε.
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JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2025
·Vol. 29
·期 13
·e70688
·
IF 4.2
Li‐Ping Kang,Cong Xu,Pan Xu,Dong‐Hui Huang,Ze‐Bo Jiang
Non‐small cell lung cancer (NSCLC) stands as a predominant cause of cancer‐related mortality worldwide. Brazilin, an active isoflavonoid compound derived from Chinese herbs, has displayed anti‐cancer properties across various cancer cell lines. However, the precise anti‐tumour mechanism of Brazilin in NSCLC remains incompletely understood. In this paper, we demonstrated that Brazilin treatment significantly reduced the proliferation of NSCLC cells and induced apoptosis. Additionally, Brazilin caused G2 cell cycle arrest in NSCLC cells, characterised by decreased expression of Cyclin B1 and increased expression of P21. Brazilin also induced mitochondrial dysfunction and ROS production in NSCLC cells. Mechanistically, Brazilin treatment significantly activated the STING pathway and upregulated the expression of CXCL10, CXCL9, and CCL5 in NSCLC cell lines. Notably, the inhibition of the STING pathway with H‐151 enhances cell viability, suggesting STING is involved in Brazilin‐induced apoptosis. These findings underscore Brazilin as a promising anti‐cancer agent for NSCLC.
研究领域:
肿瘤学
·
药理学
·
分子生物学
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ARCHIVES OF VIROLOGY
·
2024
·Vol. 169
·期 4
·1-10
·
IF 2.5
Yuan Juan,Pan Jianli,Zhang Xiaofang,Gao Rui
Triple motif protein 21 (TRIM21) has an antiviral function that inhibits various viral infections. However, its role in the progress of influenza A virus (IAV) infection is unclear. In this study, we investigated the role and molecular mechanism of TRIM21 in IAV infection. RT-qPCR was used to determine the level of TRIM21 mRNA, and ELISA was used to measure the levels of IFN-α, IFN-β, IL-6, and TNF-α. The levels of the TRIM21, NP, TBK1, IRF3, p-TBK1, and p-IRF3 proteins were estimated by Western blot. The results showed that, after IAV infection, TRIM21 was upregulated in clinical patient serum and A549 cells, and this was correlated with the IFN response. Overexpression of TRIM21 reduced IAV replication and transcription in in vitro cell experiments. TRIM21 also increased IFN-α and IFN-β levels and decreased IL-6 and TNF-α levels in A549 cells. In addition, overexpression of TRIM21 inhibited IAV-induced apoptosis. Further experiments demonstrated that TBK1-IRF3 signaling was activated by TRIM21 and was involved in the inhibitory effect of TRIM21 on virus replication. In summary, our study suggests that TRIM21 inhibits viral replication by activating the TBK1-IRF3 signaling pathway, further inhibiting the infection process of IAV.
CAS / MDL:
研究领域:
病毒学
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免疫学
·
分子生物学
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IMMUNITY
·
2021
·
IF 31.745
Run Fang,Qifei Jiang,Yukun Guan,Pengfei Gao,Rui Zhang,Zhen Zhao,Zhengfan Jiang
Summary Activation of the cyclic guanosine monophosphate (GMP)-AMP (cGAMP) sensor STING requires its translocation from the endoplasmic reticulum to the Golgi apparatus and subsequent polymerization. Using a genome-wide CRISPR-Cas9 screen to define factors critical for STING activation in cells, we identified proteins critical for biosynthesis of sulfated glycosaminoglycans (sGAGs) in the Golgi apparatus. Binding of sGAGs promoted STING polymerization through luminal, positively charged, polar residues. These residues are evolutionarily conserved, and selective mutation of specific residues inhibited STING activation. Purified or chemically synthesized sGAGs induced STING polymerization and activation of the kinase TBK1. The chain length and O -linked sulfation of sGAGs directly affected the level of STING polymerization and, therefore, its activation. Reducing the expression of Slc35b2 to inhibit GAG sulfation in mice impaired responses to vaccinia virus infection. Thus, sGAGs in the Golgi apparatus are necessary and sufficient to drive STING polymerization, providing a mechanistic understanding of the requirement for endoplasmic reticulum (ER)-to-Golgi apparatus translocation for STING activation.
研究领域:
免疫学
·
细胞生物学
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分子生物学
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高影响因子
IMMUNOLOGY LETTERS
·
2023
·
IF 4.4
Xiaohui Xia,Zhao Yang,Jiangwei Zhang,Xiongjie Fu,Bin Han,Qijiang Xiong,Anyong Yu
Background Intracerebral hemorrhage (ICH) is a serious medical problem, and promising strategy is limited. Macrophage initiated brain inflammatory injury following ICH, but the molecular mechanism had not been well identified. E3 ligase Nedd4L is implicated in the pathogenesis of the inflammatory immune response. Methods In the present study, we detected the levels of Nedd4L in macrophages following ICH. Furthermore, Macrophage M1 polarization, pro-inflammatory cytokine production, BBB disruption, brain water content and neurological function were examined in ICH mice. Results Here, we demonstrated that E3 ligase Nedd4L levels of macrophage increased following ICH, promoted M1 polarization inflammation by TRAF3. Nedd4L promoted BBB disruption, as well as neurological deficits. Inhibition of Nedd4L significantly attenuated M1 polarization in vivo. Inhibition of Nedd4L decreased TRAF3 and TBK1 levels, and subsequent phosphorylation of p38 and NF-κB p65 subunit following ICH. Conclusions Our data demonstrated that Nedd4L was involved in the pathogenesis of ICH, which promoted inflammatory responses and exacerbated brain damage by TRAF3 following ICH.
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