TRIM30α Is a Negative-Feedback Regulator of the Intracellular DNA and DNA Virus-Triggered Response by Targeting STING

Wang, Yanming; Lian, Qiaoshi; Yang, Bo; Yan, Shanshan; Zhou, Haiyan; He, Long; Lin, Guomei; Lian, Zhe‐Xiong; Jiang, Zhengfan; Sun, Bing

doi:10.1371/journal.ppat.1005012

Cited by 142 publications

(126 citation statements)

References 32 publications

(38 reference statements)

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“…Furthermore, it was reported that STING can also undergo lysosomal degradation (38). To test whether proteasomal degradation may be involved in the decrease of STING levels after stimulation of BMDCs with c‐di‐AMP or cGAMP, we conducted experiments in the presence of MG132, which is used as an inhibitor of proteasome activity (32, 36). Although MG132 could attenuate CDN‐dependent degradation of STING, involvement of the proteasome could not be confirmed.…”

Section: Resultsmentioning

confidence: 99%

Cyclic dinucleotides modulate induced type I IFN responses in innate immune cells by degradation of STING

et al. 2017

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The cyclic dinucleotides, GMP-AMP (cGAMP) and c-di-AMP [bis-(39,59)-cyclic dimeric AMP], are potent type I IFN inducers via STING-TBK1-IRF3 cascade. They are promising adjuvants that promote antigen-specific humoral and cellular immune responses in different preclinical models; however, an optimal outcome of vaccination depends on a balanced immune activation. Here, we characterize the process of IFN-b induction by c-di-AMP and cGAMP in an in vitro model on the basis of primary mouse dendritic cells. Results obtained show decreased IFN-b production upon prolonged cell stimulation. We demonstrate that this effect depends on c-di-AMP/cGAMP-mediated down-regulation of stimulator of IFN gene (STING) protein levels. These results were confirmed by using human peripheral blood mononuclear cell-derived dendritic cells. Studies performed to explore the potential mechanism of STING modulation suggested proteolytic degradation to be a contributing factor to the observed decrease in cellular STING levels. Our work contributes to the elucidation of the molecular mode of action of vaccine constituents, which, in turn, is a prerequisite for the rational design of vaccines with predictable efficacy and safety profiles-Rueckert, C., Rand, U., Roy, U., Kasmapour, B., Strowig, T., Guzmán, C. A. Cyclic dinucleotides (CDNs), such as bis-(39,59)-cyclic dimeric GMP and c-di-AMP [bis-(39,59)-cyclic dimeric AMP], are known to be produced by prokaryotes and to function as second messengers in motility, proliferation, and developmental processes (1-3). Recently, the enzyme, cyclic GMP-AMP (cGAMP) synthase, which synthesizes cGAMP after binding to cytosolic double-stranded DNA in mammalian cells, was identified. The CDN cGAMP acts as a second messenger within the cytoplasm by binding and activating the stimulator of IFN genes (STING) (4-8). STING activation can play a central role in the induction of type I IFNs and inflammatory cytokine genes, which, in turn, are pivotal, for example, to establish cellular antiviral responses (9). Furthermore, type I IFNs also strongly contribute to the induction of innate immune signaling that finally results in generation of cellular and humoral immune responses against invading pathogens (10). Thus, CDNs can act as pathogen-associated molecular patterns that function as immune enhancers in the background of infections (11-16). They have also been reported by us and others to be efficient adjuvants in preclinical models (17)(18)(19)(20). The CDNs c-di-AMP and cGAMP enhance antigen-specific humoral responses, induce balanced T helper (T h )1/T h 2/T h 17-cell responses, and promote activation of cytotoxic T lymphocytes (CTLs) when formulated with an antigen and administered by systemic or mucosal routes (17,20). Such T h and CTL responses are critical to control pathogens that cannot be neutralized by Ab responses. Our previous studies have demonstrated that the T h response profile can be shaped by the selection of an appropriate CDN as adjuvant. In this regard, cGAMP is recommended as an adj...

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Section: Resultsmentioning

confidence: 99%

Cyclic dinucleotides modulate induced type I IFN responses in innate immune cells by degradation of STING

et al. 2017

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“…The autophagy‐associated kinase ULK1 is indirectly activated by STING signaling and phosphorylates STING after it traffics to the Golgi to promote its degradation . EIF3S5, TRIM29, TRIM30α, and RNF5 also target STING for degradation by K48‐linked ubiquitination . RNF26 blocks RNF5 ubiquitination by adding a K11‐linked ubiquitin .…”

Section: Basic Biology Of the Sting Pathwaymentioning

confidence: 99%

STING pathway agonism as a cancer therapeutic

Flood

Higgs

et al. 2019

Immunological Reviews

205

161

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The fact that a subset of human cancers showed evidence for a spontaneous adaptive immune response as reflected by the T cell‐inflamed tumor microenvironment phenotype led to the search for candidate innate immune pathways that might be driving such endogenous responses. Preclinical studies indicated a major role for the host STING pathway, a cytosolic DNA sensing pathway, as a proximal event required for optimal type I interferon production, dendritic cell activation, and priming of CD8+ T cells against tumor‐associated antigens. STING agonists are therefore being developed as a novel cancer therapeutic, and a greater understanding of STING pathway regulation is leading to a broadened list of candidate immune regulatory targets. Early phase clinical trials of intratumoral STING agonists are already showing promise, alone and in combination with checkpoint blockade. Further advancement will derive from a deeper understanding of STING pathway biology as well as mechanisms of response vs resistance in individual cancer patients.

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“…Phosphorylated on Ser366 by TBK1, STING interacts with and activates IRF3, thus inducing IFNβ upregulation; STING also drives NF-κB phosphorylation, nuclear translocation, and target gene expression [33]. As a negative regulatory feedback mechanism to prevent the overstimulation of innate immune genes, E3 ligases are responsible for ubiquitin-dependent STING degradation in viral infections [34, 35]. …”

Section: Cytosolic Nucleic Acid Sensing Pathwaysmentioning

confidence: 99%

Crosstalk between Cytoplasmic RIG-I and STING Sensing Pathways

Zevini

Olagnier

Hiscott

2017

Trends in Immunology

259

183

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Detection of evolutionary conserved molecules on microbial pathogens by host immune sensors represents the initial trigger of the immune response against infection. Cytosolic receptors sense viral and intracellular bacterial genomes, as well as nucleic acids produced during replication. Once activated, these sensors trigger multiple signaling cascades, converging on the production of type I interferons and proinflammatory cytokines. Although distinct classes of receptors are responsible for the RNA and DNA sensing, the downstream signaling components are physically and functionally interconnected. This review will highlight the importance of the crosstalk between RIG-I-MAVS RNA sensing and the cGAS-STING DNA sensing pathways in potentiating efficient antiviral responses. The potential of cGAS-STING manipulation as a component of cancer immunotherapy will also be reviewed.

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TRIM30α Is a Negative-Feedback Regulator of the Intracellular DNA and DNA Virus-Triggered Response by Targeting STING

Cited by 142 publications

References 32 publications

Cyclic dinucleotides modulate induced type I IFN responses in innate immune cells by degradation of STING

Cyclic dinucleotides modulate induced type I IFN responses in innate immune cells by degradation of STING

STING pathway agonism as a cancer therapeutic

Crosstalk between Cytoplasmic RIG-I and STING Sensing Pathways

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