UNC93B1 curbs cytosolic DNA signaling by promoting STING degradation

He, Zhenliang; Ye, Sichao; Xing, Yifan; Jiu, Yaming; Zhong, Jin

doi:10.1002/eji.202048901

Cited by 15 publications

(8 citation statements)

References 43 publications

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“…During our generation of Unc93b1 -/--deficient (Unc93b1 −/− ) mice, a recent in vitro study showed that UNC93B1 deficiency augments innate immune responses to cytosolic DNA stimulation and DNA virus infection via stabilizing STING and potentiating the cGAS-STING signaling pathway, 23 which is consistent with our findings. In addition, our in vivo study demonstrates that Unc93b1 −/− mice are more resistant to HSV-1 infection with higher IFN-β production and IFN-β, ISG54, and ISG56 transcriptions than WT littermates, corroborating our conclusion.…”

supporting

confidence: 91%

UNC93B1 attenuates the cGAS–STING signaling pathway by targeting STING for autophagy–lysosome degradation

Zhu

Zhang

et al. 2022

Journal of Medical Virology

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Stimulator of interferon genes (STING) is a pivotal innate immune adaptor, and its functions during DNA virus infections have been extensively documented. However, its homeostatic regulation is not well understood. Our study demonstrates that Unc-93 homolog B1 (UNC93B1) is a crucial checker for STING to prevent hyperactivation. Ectopic expression of UNC93B1 attenuates IFN-β promoter activity and the transcriptions of IFN-β, ISG54, and ISG56 genes. Moreover, UNC93B1 also blocks the IRF3 nuclear translocation induced by ectopic expression of both cyclic GMP-AMP synthase (cGAS) and STING and reduces the stability of STING by facilitating its autophagy-lysosome degradation, which can be reversed by lysosome inhibitors. Mechanistically, UNC93B1 interacts with STING and suppresses STING-activated downstream signaling by delivering STING to the lysosomes for degradation, depending on its trafficking capability. UNC93B1 knockout in human embryonic kidney 293T cells facilitates IFN-β promoter activity, IFN-β, ISG54, and ISG56 transcriptions, and IRF3 nuclear translocation induced by ectopic expression of cGAS and STING. Infected with herpes simplex virus-1 (HSV-1), UNC93B1 knockdown BJ cells or primary peritoneal macrophages from Unc93b1-deficient (Unc93b1 −/− ) mice show enhanced IFN-β, ISG54, and ISG56 transcriptions, TBK1 phosphorylation, and reduced STING degradation and viral replication. In addition, Unc93b1 −/− mice exhibit higher IFN-β, ISG54, and ISG56 transcriptions and lower mortality upon HSV-1 infection in vivo. Collectively, these findings demonstrate that UNC93B1 attenuates the cGAS-STING signaling pathway by targeting STING for autophagy-lysosome degradation and provide novel insights into the function of UNC93B1 in antiviral innate immunity.

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supporting

confidence: 91%

UNC93B1 attenuates the cGAS–STING signaling pathway by targeting STING for autophagy–lysosome degradation

Zhu

Zhang

et al. 2022

Journal of Medical Virology

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“…TLR2, 7, 9, and other subtypes also contribute to viral recognition (53, 54) (Figure 2). UNC93B1 is a multi-transmembrane protein that plays a crucial role in necleic-acid-sensing TLR signaling (55). Studies have shown that the UNC93B1 regulates the TLR7/9 signaling pathway by transferring TLR7 and 9 to endolysosomes (56).…”

Section: Primary Immune Response In Hsvementioning

confidence: 99%

When herpes simplex virus encephalitis meets antiviral innate immunity

Zhang

Zhang²,

Li³

et al. 2023

Front. Immunol.

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Herpes simplex virus (HSV) is the most common pathogen of infectious encephalitis, accounting for nearly half of the confirmed cases of encephalitis. Its clinical symptoms are often atypical. HSV PCR in cerebrospinal fluid is helpful for diagnosis, and the prognosis is usually satisfactory after regular antiviral treatment. Interestingly, some patients with recurrent encephalitis have little antiviral effect. HSV PCR in cerebrospinal fluid is negative, but glucocorticoid has a significant effect after treatment. Specific antibodies, such as the NMDA receptor antibody, the GABA receptor antibody, and even some unknown antibodies, can be isolated from cerebrospinal fluid, proving that the immune system contributes to recurrent encephalitis, but the specific mechanism is still unclear. Based on recent studies, we attempt to summarize the relationship between herpes simplex encephalitis and innate immunity, providing more clues for researchers to explore this field further.

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“…Many endosomal interactors with STING1 have been identified at the late activation stage in RAW264.7 cells, providing an integrated mechanism to control STING1 trafficking ( 43 ). Unc-93 homolog B1, TLR signaling regulator (UNC93B1) is a chaperone of endosomal toll-like receptors (TLRs) and acts as a repressor of STING1 activation by anchoring STING1 in the endosomes of human and mouse fibroblasts ( 67 ). Endosomal TLRs play a role in the activation of B cells in the context of autoimmune diseases ( 68 ).…”

Section: Roles Of Sting1 In Organellesmentioning

confidence: 99%

STING1 in Different Organelles: Location Dictates Function

2022

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Stimulator of interferon response cGAMP interactor 1 (STING1), also known as TMEM173, is an immune adaptor protein that governs signal crosstalk that is implicated in many physiological and pathological processes. Although it has been established that STING1 traffics from the endoplasmic reticulum (ER) to Golgi apparatus (Golgi) upon DNA-triggered activation, emerging evidence reveals that STING1 can be transported to different organelles, which dictate its immune-dependent (e.g., the production of type I interferons and pro-inflammatory cytokines) and -independent (e.g., the activation of autophagy and cell death) functions. In this brief review, we outline the roles of STING1 in different organelles (including the ER, ER-Golgi intermediate compartment, Golgi, mitochondria, endosomes, lysosomes, and nucleus) and discuss the potential relevance of these roles to diseases and pharmacological interventions.

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UNC93B1 curbs cytosolic DNA signaling by promoting STING degradation

Cited by 15 publications

References 43 publications

UNC93B1 attenuates the cGAS–STING signaling pathway by targeting STING for autophagy–lysosome degradation

UNC93B1 attenuates the cGAS–STING signaling pathway by targeting STING for autophagy–lysosome degradation

When herpes simplex virus encephalitis meets antiviral innate immunity

STING1 in Different Organelles: Location Dictates Function

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