The Dengue virus protease NS2B3 cleaves cyclic GMP-AMP synthase to suppress cGAS activation

Bhattacharya, Madhurima; Bhowmik, Debipreeta; Tian, Yuan; He, Hongbin; Zhu, Fanxiu; Yin, Qian

doi:10.1016/j.jbc.2023.102986

Cited by 9 publications

(7 citation statements)

References 33 publications

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“…By analogy to the better characterized human cGAS, cleavage by 3Cpro would excise the N-terminal disordered region of cGAS (1–134 in po cGAS and 1–160 in h cGAS) known to bind DNA and enhance cGAMP production [ 54 ]. Although the C-terminal nucleotidyltransferase domain (NTase) is sufficient to synthesize cGAMP in the presence of dsDNA [ 55 ], Bhattacharya et al showed using an in vitro recombination system that truncation of the N-terminal domain reduced the affinity and competed for binding of the C-terminal NTase domain to dsDNA inhibiting cGAMP production [ 29 ]. Cleavage by Lpro at positions 322–330 would release the C-terminal zinc ribbon/thumb domain and several residues involved in two DNA-binding sites (termed A and B sites), all required for activity [ 5 ] (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Using recombinant proteins and in vitro cleavage assays, Bhattacharya et al showed that the DENV NS2B3 protease is capable of cleaving human cGAS in the N-terminus potentially disrupting the C-terminal enzymatic activity of the protein [ 29 ]. Also, a recent work showed that the 3C protease encoded by the Seneca valley virus (SVV) can cleave porcine cGAS overexpressed in human cells [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

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The antiviral response triggered by the cGAS/STING pathway is subverted by the foot-and-mouth disease virus proteases

Sanz,

Polo,

Rodríguez-Pulido

et al. 2024

Cell. Mol. Life Sci.

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Propagation of viruses requires interaction with host factors in infected cells and repression of innate immune responses triggered by the host viral sensors. Cytosolic DNA sensing pathway of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) is a major component of the antiviral response to DNA viruses, also known to play a relevant role in response to infection by RNA viruses, including foot-and-mouth disease virus (FMDV). Here, we provide supporting evidence of cGAS degradation in swine cells during FMDV infection and show that the two virally encoded proteases, Leader (Lpro) and 3Cpro, target cGAS for cleavage to dampen the cGAS/STING-dependent antiviral response. The specific target sequence sites on swine cGAS were identified as Q140/T141 for the FMDV 3Cpro and the KVKNNLKRQ motif at residues 322–330 for Lpro. Treatment of swine cells with inhibitors of the cGAS/STING pathway or depletion of cGAS promoted viral infection, while overexpression of a mutant cGAS defective for cGAMP synthesis, unlike wild type cGAS, failed to reduce FMDV replication. Our findings reveal a new mechanism of RNA viral antagonism of the cGAS-STING innate immune sensing pathway, based on the redundant degradation of cGAS through the concomitant proteolytic activities of two proteases encoded by an RNA virus, further proving the key role of cGAS in restricting FMDV infection.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The antiviral response triggered by the cGAS/STING pathway is subverted by the foot-and-mouth disease virus proteases

Sanz,

Polo,

Rodríguez-Pulido

et al. 2024

Cell. Mol. Life Sci.

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show abstract

“…cGAMP, the second messenger of the cGAS-STING pathway, is critical for this host innate immune responses against viral infections. Accordingly, some viruses could degrade 2'3'-cGAMP using specific enzymes to restrict cGAMP-STING signaling [39,40], while some could cleave or repress cGAS to decrease cGAMP production [41][42][43][44]. Therefore, the strategies to enhance cGAMP (or cGAMP analog)-induced STING innate immune response may have potentials in antiviral treatment.…”

Section: Discussionmentioning

confidence: 99%

Microtubule disruption synergizes with STING signaling to show potent and broad-spectrum antiviral activity

Han,

Wang,

Han

et al. 2024

PLoS Pathog

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The activation of stimulator of interferon genes (STING) signaling induces the production of type I interferons (IFNs), which play critical roles in protective innate immunity for the host to defend against viral infections. Therefore, achieving sustained or enhanced STING activation could become an antiviral immune strategy with potential broad-spectrum activities. Here, we discovered that various clinically used microtubule-destabilizing agents (MDAs) for the treatment of cancer showed a synergistic effect with the activation of STING signaling in innate immune response. The combination of a STING agonist cGAMP and a microtubule depolymerizer MMAE boosted the activation of STING innate immune response and showed broad-spectrum antiviral activity against multiple families of viruses. Mechanistically, MMAE not only disrupted the microtubule network, but also switched the cGAMP-mediated STING trafficking pattern and changed the distribution of Golgi apparatus and STING puncta. The combination of cGAMP and MMAE promoted the oligomerization of STING and downstream signaling cascades. Importantly, the cGAMP plus MMAE treatment increased STING-mediated production of IFNs and other antiviral cytokines to inhibit viral propagation in vitro and in vivo. This study revealed a novel role of the microtubule destabilizer in antiviral immune responses and provides a previously unexploited strategy based on STING-induced innate antiviral immunity.

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“…For example, DENV NS2B protease targets cGAS for lysosomal degradation to dampen cGAS activation [ 15 ]. Recently, DENV NS2B3 also was reported to cleave hcGAS NT, suggesting different ways of DENV targeting cGAS for immune evasion [ 41 ]. Another study showed that DENV1-4 cleaved human STING within and RG motif between residues 78 and 79 but does not target non-human primates STING [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Species-specific cleavage of cGAS by picornavirus protease 3C disrupts mitochondria DNA-mediated immune sensing

Yan,

Wu,

Yuan

et al. 2023

PLoS Pathog

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RNA viruses cause numerous infectious diseases in humans and animals. The crosstalk between RNA viruses and the innate DNA sensing pathways attracts increasing attention. Recent studies showed that the cGAS-STING pathway plays an important role in restricting RNA viruses via mitochondria DNA (mtDNA) mediated activation. However, the mechanisms of cGAS mediated innate immune evasion by RNA viruses remain unknown. Here, we report that seneca valley virus (SVV) protease 3C disrupts mtDNA mediated innate immune sensing by cleaving porcine cGAS (pcGAS) in a species-specific manner. Mechanistically, a W/Q motif within the N-terminal domain of pcGAS is a unique cleavage site recognized by SVV 3C. Three conserved catalytic residues of SVV 3C cooperatively contribute to the cleavage of pcGAS, but not human cGAS (hcGAS) or mouse cGAS (mcGAS). Additionally, upon SVV infection and poly(dA:dT) transfection, pcGAS and SVV 3C colocalizes in the cells. Furthermore, SVV 3C disrupts pcGAS-mediated DNA binding, cGAMP synthesis and interferon induction by specifically cleaving pcGAS. This work uncovers a novel mechanism by which the viral protease cleaves the DNA sensor cGAS to evade innate immune response, suggesting a new antiviral approaches against picornaviruses.

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The Dengue virus protease NS2B3 cleaves cyclic GMP-AMP synthase to suppress cGAS activation

Cited by 9 publications

References 33 publications

The antiviral response triggered by the cGAS/STING pathway is subverted by the foot-and-mouth disease virus proteases

The antiviral response triggered by the cGAS/STING pathway is subverted by the foot-and-mouth disease virus proteases

Microtubule disruption synergizes with STING signaling to show potent and broad-spectrum antiviral activity

Species-specific cleavage of cGAS by picornavirus protease 3C disrupts mitochondria DNA-mediated immune sensing

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