Post-Translational Modifications of STING: A Potential Therapeutic Target

Kang, Jiaqi; Wu, Jie; Liu, Qinjie; Wu, Xiuwen; Zhao, Yun; Ren, Jianan

doi:10.3389/fimmu.2022.888147

Cited by 25 publications

(11 citation statements)

References 169 publications

(204 reference statements)

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“…We observed differential STING and phosphor-STING expression level in CBD treated and control cells. To examine if CBD treatment affects gene expression of kinases and phosphatases that regulate STING function, we searched our RNAseq database for differential expression of these genes ( 53 ). We observed no significant change of TBK1 and minimum increase in ULK1 expression (1.18 fold) by CBD treatment ( 54 , 55 ).…”

Section: Discussionmentioning

confidence: 99%

Cannabidiol modulates expression of type I IFN response genes and HIV infection in macrophages

Tomer

Suryawanshi

et al. 2022

Front. Immunol.

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Cannabis (Cannabis sativa) is a widely used drug in the United States and the frequency of cannabis use is particularly high among people living with HIV (PLWH). One key component of cannabis, the non-psychotropic (−)-cannabidiol (CBD) exerts a wide variety of biological actions, including anticonvulsive, analgesic, and anti-inflammatory effects. However, the exact mechanism of action through which CBD affects the immune cell signaling remains poorly understood. Here we report that CBD modulates type I interferon responses in human macrophages. Transcriptomics analysis shows that CBD treatment significantly attenuates cGAS-STING-mediated activation of type I Interferon response genes (ISGs) in monocytic THP-1 cells. We further showed that CBD treatment effectively attenuates 2’3-cGAMP stimulation of ISGs in both THP-1 cells and primary human macrophages. Interestingly, CBD significantly upregulates expression of autophagy receptor p62/SQSTM1. p62 is critical for autophagy-mediated degradation of stimulated STING. We observed that CBD treated THP-1 cells have elevated autophagy activity. Upon 2’3’-cGAMP stimulation, CBD treated cells have rapid downregulation of phosphorylated-STING, leading to attenuated expression of ISGs. The CBD attenuation of ISGs is reduced in autophagy deficient THP-1 cells, suggesting that the effects of CBD on ISGs is partially mediated by autophagy induction. Lastly, CBD decreases ISGs expression upon HIV infection in THP-1 cells and human primary macrophages, leading to increased HIV RNA expression 24 hours after infection. However, long term culture with CBD in infected primary macrophages reduced HIV viral spread, suggesting potential dichotomous roles of CBD in HIV replication. Our study highlights the immune modulatory effects of CBD and the needs for additional studies on its effect on viral infection and inflammation.

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Section: Discussionmentioning

confidence: 99%

Cannabidiol modulates expression of type I IFN response genes and HIV infection in macrophages

Tomer

Suryawanshi

et al. 2022

Front. Immunol.

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“…The activation of STING leads to the activation of the TBK1–IRF3-signaling-mediated induction of IFN-I and antiviral interferon-stimulated genes [ 7 , 9 , 158 , 159 ]. Various post-translational modifications (PTMs) of STING that modulate the activation of STING-dependent signaling, such as ubiquitination, phosphorylation, SUMOylation, and acetylation, have been reported [ 160 , 161 ]. However, few studies have described the role of PTMs in STING in the context of HIV-1 replication.…”

Section: Isg15 Is a Regulator Of Hiv-1 Dna Sensingmentioning

confidence: 99%

The ISG15-Protease USP18 Is a Pleiotropic Enhancer of HIV-1 Replication

Lin,

Kuffour,

et al. 2024

Viruses

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The innate immune response to viruses is formed in part by interferon (IFN)-induced restriction factors, including ISG15, p21, and SAMHD1. IFN production can be blocked by the ISG15-specific protease USP18. HIV-1 has evolved to circumvent host immune surveillance. This mechanism might involve USP18. In our recent studies, we demonstrate that HIV-1 infection induces USP18, which dramatically enhances HIV-1 replication by abrogating the antiviral function of p21. USP18 downregulates p21 by accumulating misfolded dominant negative p53, which inactivates wild-type p53 transactivation, leading to the upregulation of key enzymes involved in de novo dNTP biosynthesis pathways and inactivated SAMHD1. Despite the USP18-mediated increase in HIV-1 DNA in infected cells, it is intriguing to note that the cGAS-STING-mediated sensing of the viral DNA is abrogated. Indeed, the expression of USP18 or knockout of ISG15 inhibits the sensing of HIV-1. We demonstrate that STING is ISGylated at residues K224, K236, K289, K347, K338, and K370. The inhibition of STING K289-linked ISGylation suppresses its oligomerization and IFN induction. We propose that human USP18 is a novel factor that potentially contributes in multiple ways to HIV-1 replication.

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“…STING is known to undergo diverse post-translational modifications, including phosphorylation, palmitoylation, ubiquitination, SUMOylation, nitro-alkylation, glycosylation, carbonylation, reversible oxidation, and et al. ( 58 – 60 ). Palmitoylation of STING at the trans-Golgi network (TGN) is essential for the activation of STING.…”

Section: Cgas-sting Pathwaymentioning

confidence: 99%

Function and regulation of cGAS-STING signaling in infectious diseases

Luo

et al. 2023

Front. Immunol.

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The efficacious detection of pathogens and prompt induction of innate immune signaling serve as a crucial component of immune defense against infectious pathogens. Over the past decade, DNA-sensing receptor cyclic GMP-AMP synthase (cGAS) and its downstream signaling adaptor stimulator of interferon genes (STING) have emerged as key mediators of type I interferon (IFN) and nuclear factor-κB (NF-κB) responses in health and infection diseases. Moreover, both cGAS-STING pathway and pathogens have developed delicate strategies to resist each other for their survival. The mechanistic and functional comprehension of the interplay between cGAS-STING pathway and pathogens is opening the way for the development and application of pharmacological agonists and antagonists in the treatment of infectious diseases. Here, we briefly review the current knowledge of DNA sensing through the cGAS-STING pathway, and emphatically highlight the potent undertaking of cGAS-STING signaling pathway in the host against infectious pathogenic organisms.

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Post-Translational Modifications of STING: A Potential Therapeutic Target

Cited by 25 publications

References 169 publications

Cannabidiol modulates expression of type I IFN response genes and HIV infection in macrophages

Cannabidiol modulates expression of type I IFN response genes and HIV infection in macrophages

The ISG15-Protease USP18 Is a Pleiotropic Enhancer of HIV-1 Replication

Function and regulation of cGAS-STING signaling in infectious diseases

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