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Seneca Valley Virus (SVV) 3C protease is essential for viral polyprotein processing and virion assembly. Meanwhile, it has evolved to cleave and antagonize the multiple innate immune proteins, enabling viral immune evasion. Inhibitors of 3C protease are therefore powerful antiviral agents. Among these, antiviral peptide inhibitors hold particular promise because of their high specificity, strong efficacy, and broad-spectrum activity, and minimal side effects. Here, we developed a dimerization-dependent red fluorescent protein (ddRFP) biosensor system to screen anti-SVV 3C peptides and identified a substrate-competitive decapeptide (P5) that markedly suppresses 3C protease activity. P5 inhibited 3C-mediated cleavage of multiple key immune proteins, including porcine cGAS (pcGAS), porcine Gasdermin A (pGSDMA) and porcine Pro-IL-1β (sPro-IL-1β). Mechanistically, P5 directly interacted with the catalytic His48 site of 3C protease through hydrogen bonding. Remarkably, P5 restored the formation of cGAS-DNA liquid-liquid phase separation (LLPS) by competitively blocking 3C cleavage activity, thereby enhancing cGAS activity and downstream antiviral interferon signaling. Furthermore, P5 demonstrated favorable cellular permeability, low cytotoxicity, good stability and robust antiviral activity. Our findings establish P5 as a highly promising peptide inhibitor of SVV 3C protease with strong translational potential.

Stimulator of interferon genes (STING) is a central player of innate immunity, coordinating host defense against viral infection and cancer. While the canonical architectures of apo-STING and ligand-bound STING have been established, current knowledge is limited to a subset of species, and a comprehensive cross-species, ligand-resolved structural atlas remains incomplete. Here, we determined the high-resolution crystal structures of duck and bovine STING ligand-binding domains (LBDs) bound to 2′3′-cGAMP and of duck, bovine, and human STING LBDs bound to the non-nucleotide agonist diABZI3. In the 2′3′-cGAMP complexes, the lid regions were ordered and completely covered the ligand-binding pocket, whereas in the diABZI3 complexes, the lid regions were completely disordered. In human and bovine STING, 2′3′-cGAMP induced a more closed dimer conformation than diABZI3, while duck STING exhibited minimal differences in closure between the two ligands. Strikingly, non-reducing SDS-PAGE revealed a distinct disulfide-linked tetramer in duck STING, which is abolished by the C195S mutation. Within the crystal lattice of the duck STING LBD–2′3′-cGAMP complex, we observed a unique Z-shaped tetramer stabilized by an interfacial disulfide bond between C195 and a network of polar interactions. Disrupting this interface, either by the C195S mutation or by ligand stimulation with 2′3′-cGAMP or diABZI3, relieved the tetrameric constraint and amplified STING signaling, establishing this tetramer as a duck-specific autoinhibitory assembly. These findings expand the structural repertoire of STING oligomeric assemblies, fill the structural gap for duck STING, and provide a comparative structural framework for species-specific STING regulation.

Most, if not all, of the hydrogenation reactions are catalyzed by organometallic complexes (M) or heterogeneous metal catalysts, but to improve both the activity and selectivity simultaneously in one reaction via a rational combination of the two types of catalysts remains largely unexplored. In this work, we report a hydrogenation mode though H species relay from supported metal nanoparticles (NPs) to M, where the former is responsible for H 2 dissociation, and M is for further hydride transferring to reactants. The synergy between metal NPs and M yields an efficient NAD(P)H regeneration system with >99% selectivity and a magnitude higher activity than the corresponding metal NPs and M. The modularizing of hydrogenation reaction into hydrogen activation with metal NPs and substrate activation with metal complex paves a new way to rationally address the challenging hydrogenation reactions. Homogenous and heterogeneous catalysts were applied separately and rarely catalyzed a target reaction synergistically. Herein, the authors identify the synergy effect of these two types of catalysts in NAD(P)H regeneration via relay hydrogenation.

The low-temperature hydrogenation of CO 2 to methanol is of great significance for the recycling of this greenhouse gas to valuable products, however, it remains a great challenge due to the trade-off between catalytic activity and selectivity. Here, we report that CO 2 can dissociate at sulfur vacancies in MoS 2 nanosheets to yield surface-bound CO and O at room temperature, thus enabling a highly efficient low-temperature hydrogenation of CO 2 to methanol. Multiple in situ spectroscopic and microscopic characterizations combined with theoretical calculations demonstrated that in-plane sulfur vacancies drive the selective hydrogenation of CO 2 to methanol by inhibiting deep hydrogenolysis to methane, whereas edge vacancies facilitate excessive hydrogenation to methane. At 180 °C, the catalyst achieved a 94.3% methanol selectivity at a CO 2 conversion of 12.5% over the in-plane sulfur vacancy-rich MoS 2 nanosheets, which notably surpasses those of previously reported catalysts. This catalyst exhibited high stability for over 3,000 hours without any deactivation, rendering it a promising candidate for industrial application. The catalytic hydrogenation of CO 2 to methanol is a crucial reaction for the recycling of this greenhouse gas, although the selection and related performance of commercial catalysts is still limited. Now, the authors introduce sulfur vacancy-rich MoS 2 nanosheets as a superior catalyst for this process, rivalling the commercial benchmark system.

Cyclic GMP-AMP synthase (cGAS) is a key sensor of double-stranded DNA (dsDNA), initiating oligomerization and phase separation to drive immune responses against pathogens and endogenous damage. Porcine circovirus (PCV) induces immunosuppression, heightening susceptibility to secondary infections, but the underlying mechanisms remain unclear. Here, we report PCV type 2d (PCV2d) infection fails to induce type I interferons (IFN-I) and significantly suppresses IFN-I production upon poly (dA:dT) stimulation in a dose-dependent manner. Mechanistically, the replication-related protein (Rep) proteins of PCV2, PCV3 and PCV4 inhibit cGAS-mediated IFN-I induction by competitively binding dsDNA, thereby disrupting cGAS oligomerization and phase separation. Interestingly, Rep also suppresses mitochondria DNA-induced cGAS activation. We further identify Rep residues Q12 and R199-W202 as key regions facilitating dsDNA binding. Our findings reveal a previously unrecognized mechanism by which circovirus Rep antagonizes cGAS activation, providing new insights into PCV-induced immunosuppression.

Alpha-herpesviruses, including pseudorabies virus (PRV) and herpes simplex virus type 1 (HSV-1), cause severe diseases in a wide range of hosts. However, the precise mechanisms of immune evasion by alpha-herpesviruses remains elusive, hindering the development of broad-spectrum antiviral vaccines and drugs. Here, we demonstrate that the immediate early protein US1, encoded by alpha-herpesviruses, directly interacts with cGAS, suppressing its dsDNA binding and enzymatic activity. Structural analysis using AlphaFold reveals a conserved overlapping region within PRV and HSV-1 US1 proteins. Deletion of these peptides leads to increased cGAS-mediated IFN-β production. Meanwhile, both synthetic and purified SUMO-fused US1 peptides significantly inhibit cGAS activity across species, with the SUMO-fused US1 peptides directly binding to the catalytic domain of cGAS. Both US1-deficient viruses (PRV-ΔUS1 and HSV-1-ΔUS1) exhibit higher IFN-β production and enhanced signaling through the cGAS-STING pathway. Importantly, mice infected with PRV-ΔUS1 or HSV-1-ΔUS1 show increased IFN-β secretion and reduced viral loads. In conclusion, overlapping peptides from US1 protein of alpha-herpesviruses antagonize cGAS-mediated innate immune responses, highlighting a promising target for the development of broad-spectrum inhibitors to counteract herpesvirus infections.

Gasdermin A (GSDMA) remains a protein shrouded in mystery, particularly regarding its regulation by virus-encoded proteases. Previous studies have identified human GSDMA (hGSDMA) as a sensor and substrate of the SpeB from group A Streptococcus , which initiates pyroptosis. However, it is not clear if viral proteases also cleave GSDMA. In this study, we show that a fragment of porcine GSDMA (pGSDMA) containing the first 252 residues constitutes the pore-forming domain responsible for inducing lytic cell death and pyroptosis. Interestingly, picornavirus Seneca Valley Virus (SVV) protease 3C cleaves both pGSDMA and hGSDMA, generating a shorter fragment that fails to associate with the plasma membrane and does not induce pyroptosis. This cleavage by SVV 3C suppresses GSDMA-mediated lactate dehydrogenase release, bactericidal activity, and lytic cell death. This study reveals how SVV subverts host inflammatory defense by disrupting GSDMA-induced pyroptosis, thereby advancing our understanding of antiviral immunity and opening avenues for treating GSDMA-associated autoimmune diseases.

Inflammasomes and interferons are two critical defense mechanisms of innate immunity, and their imbalance is a key strategy employed by viruses to evade host immune surveillance. During porcine reproductive and respiratory syndrome virus (PRRSV) infection, an arteritis virus, a characteristic “high inflammation, low interferon” immune imbalance is observed. This study identifies PRRSV non-structural protein NSP5 as a central mediator of this immune imbalance. We demonstrate that NSP5 recruits NLRP3 to the endoplasmic reticulum (ER)-mitochondrial interface, triggering ER stress and Ca 2+ leakage, which subsequently activates the NLR family pyrin domain containing 3 (NLRP3) inflammasome. Notably, a specific NSP5 mutation (G30A) abolishes its ability to activate NLRP3. PRRSV carrying this mutation exhibits suppressed NLRP3 activation and IL-1β release. Concurrently, NSP5 retains STING in the ER, preventing its trafficking and inhibiting type I interferon induction. This dual mechanism ultimately drives the high inflammation and low interferon phenotype observed during PRRSV infection. Importantly, our findings reveal that a single viral protein can orchestrate immune imbalance, suggesting a potentially widespread strategy for viral evasion of host immune surveillance.

According to previous studies, three representative avian adenoviral strains utilize coxsackievirus–adenovirus receptor (CAR) as a receptor and seem to exhibit diverse binding affinities and modes. Thus, further revealing the exact molecular mechanism underlying the interaction between different FAdVs and the attachment receptor CAR is necessary. In this study, we successfully solved the crystal structure of the FAdV-4 fiber1 knob at 1.6 Å resolution. The interaction between the fibre knob and different domains of CAR was verified by confocal microscopy, coimmunoprecipitation and surface plasmon resonance (SPR) analysis. The fibre knobs of the three representative fowl adenoviruses specifically recognized CAR domain 1 (D1), but the recognition of CAR domain 2 (D2) by chicken embryo lethal orphan (CELO) strains was weak. These results provide insights into the differences in adenovirus‒host cell interactions and have important implications for the exploration of viral invasion mechanisms.

Inflammasomes play pivotal roles in inflammation by processing and promoting the secretion of IL-1β. Caspase-1 is involved in the maturation of IL-1β and IL-18, while human caspase-4 specifically processes IL-18. Recent structural studies of caspase-4 bound to Pro-IL-18 reveal the molecular basis of Pro-IL-18 activation by caspase-4. However, the mechanism of caspase-1 processing of pro-IL-1β and other IL-1β-converting enzymes remains elusive. Here, we observed that swine Pro-IL-1β (sPro-IL-1β) exists as an oligomeric precursor unlike monomeric human Pro-IL-1β (hPro-IL-1β). Interestingly, Seneca Valley Virus (SVV) 3C protease cleaves sPro-IL-1β to produce mature IL-1β, while it cleaves hPro-IL-1β but does not produce mature IL-1β in a specific manner. When the inflammasome is blocked, SVV 3C continues to activate IL-1β through direct cleavage in porcine alveolar macrophages (PAMs). Through molecular modeling and mutagenesis studies, we discovered that the pro-domain of sPro-IL-1β serves as an ’exosite’ with its hydrophobic residues docking into a positively charged 3C protease pocket, thereby directing the substrate to the active site. The cleavage of sPro-IL-1β generates a monomeric and active form of IL-1β, initiating the downstream signaling. Thus, these studies provide IL-1β is an inflammatory sensor that directly detects viral protease through an independent pathway operating in parallel with host inflammasomes.