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Linear ubiquitination is a critical regulator of inflammatory signaling pathways. However, linearly ubiquitinated substrates and the biological significance of linear ubiquitination is incompletely understood. Here, we show that STAT1 has linear ubiquitination at Lys511 and Lys652 residues in intact cells, which inhibits STAT1 binding to the type-I interferon receptor IFNAR2, thereby restricting STAT1 activation and resulting in type-I interferon signaling homeostasis. Linear ubiquitination of STAT1 is removed rapidly by OTULIN upon type-I interferon stimulation, which facilitates activation of interferon-STAT1 signaling. Furthermore, viruses induce HOIP expression through the NF-κB pathway, which in turn increases linear ubiquitination of STAT1 and thereby inhibits interferon antiviral response. Consequently, HOIL-1L heterozygous mice have active STAT1 signaling and enhanced responses to type-I interferons. These findings demonstrate a linear ubiquitination-mediated switch between homeostasis and activation of type-I interferon signaling, and suggest potential strategies for clinical antiviral therapy. LUBAC is involved in adding linear ubiquitin chains to important immune signaling proteins. Here the authors show that this mechanism is effective in inhibiting STAT1-mediated interferon signaling, and that the deubiquitinase OTULIN can remove these linear ubiquitins from STAT1 to reactivate this antiviral signaling pathway.

During RNA virus infection, the adaptor protein MAVS recruits TRAF3 and TRAF6 to form a signalosome, which is critical to induce the production of type I interferons (IFNs) and proinflammatory cytokines. While activation of the MAVS/TRAF3/TRAF6 signalosome is well studied, the negative regulation of the signalosome remains largely unknown. Here we report that RNA viruses specifically promote the deubiquitinase OTUD1 expression by NF-κB-dependent mechanisms at the early stage of viral infection. Furthermore, OTUD1 upregulates protein levels of intracellular Smurf1 by removing Smurf1 ubiquitination. Importantly, RNA virus infection promotes the binding of Smurf1 to MAVS, TRAF3 and TRAF6, which leads to ubiquitination-dependent degradation of every component of the MAVS/TRAF3/TRAF6 signalosome and subsequent potent inhibition of IFNs production. Consistently, OTUD1-deficient mice produce more antiviral cytokines and are more resistant to RNA virus infection. Our findings reveal a novel immune evasion mechanism exploited by RNA viruses, and elucidate a negative feedback loop of MAVS/TRAF3/TRAF6 signaling mediated by the OTUD1-Smurf1 axis during RNA virus infection.

Depression is a serious public-health issue. Recent reports have suggested higher susceptibility to viral infections in depressive patients. However, how depression affects antiviral innate immune signaling remains unknown. Here, we revealed a reduction in expression of Abelson helper integration site 1 (AHI1) in the peripheral blood mononuclear cells (PBMCs) and macrophages from the patients with major depressive disorder (MDD), which leads to attenuated antiviral immune response. We found that depression-related arginine vasopressin (AVP) induces reduction of AHI1 in macrophages. Further studies demonstrated that AHI1 is a critical stabilizer of basal type-I-interferon (IFN-I) signaling. Mechanistically, AHI1 recruits OTUD1 to deubiquitinate and stabilize Tyk2, while AHI1 reduction downregulates Tyk2 and IFN-I signaling activity in macrophages from both MDD patients and depression model mice. Interestingly, we identified a clinical analgesic meptazinol that effectively stimulates AHI1 expression, thus enhancing IFN-I antiviral defense in depression model mice. Our study promotes the understanding of the signaling mechanisms of depression-mediated antiviral immune dysfunction, and reveals meptazinol as an enhancer of antiviral innate immunity in depressive patients.

Innate immunity is an important component of the immune system and serves as the first line of defense for the host against the invasion of foreign pathogens. Viperin (RSAD2), a core member of the interferon-stimulated gene (ISG) family, plays a key role in innate immunity through direct inhibition of viral replication and modulation of the host immune–metabolic network. The intracellular expression of Viperin rises markedly after viral infection or interferon-induced induction, showing a wide range of antiviral activities. In recent years, the versatility of Viperin in viral infections, autoimmune diseases, and tumor immune metabolism has been gradually revealed. Here, we summarize and discuss the gene regulatory network, molecular functions, and multi-dimensional roles of Viperin in diseases to provide a theoretical basis for the development of broad-spectrum antiviral strategies and immunometabolic therapies based on Viperin.

Hypo-peritectic steels are susceptible to interfacial cracking during thin-slab continuous casting, in which non-metallic inclusions play a critical role. This study systematically investigates the effects of inclusion type and morphology on interface cracking behavior in the steel matrix, with the aim of improving billet shell quality. Hot tensile experiments were conducted using a Gleeble 3800 thermal simulator, and a finite element–based cohesive zone model was developed to simulate inclusion-induced crack nucleation and propagation. The results demonstrate that inclusions markedly influence interfacial stress distribution and damage evolution. The maximum interfacial stresses associated with MnS, Al2O3, and composite inclusions are 20.7, 23.4, and 30.5 MPa, respectively. Owing to severe stress concentration at sharp corners, composite inclusions exhibit the earliest crack nucleation at an applied stress of 11.3 MPa and the highest energy dissipation. In all cases, cracks initially nucleate at the location of maximum tensile stress (α = 90°), propagate along the interface, and subsequently penetrate into the matrix, ultimately leading to failure. The strong agreement between numerical simulations and experimental results confirms that angular inclusions accelerate damage by disrupting matrix continuity. These findings provide theoretical guidance for improving hypo-peritectic steel quality through inclusion morphology control during continuous casting.

The microcrack initiation and evolution behavior of Fe-C alloy under uniaxial tensile loading are investigated using molecular dynamics (MD) simulations. The model is stretched along the z-axis at a strain rate of 2 × 109 s−1 and temperatures ranging from 300 to 1100 K, aiming to elucidate the microscopic deformation mechanisms during crack evolution under varying thermal conditions. The results indicate that the yield strength of Fe-C alloy decreases with a rising temperature, accompanied by a 25.2% reduction in peak stress. Within the temperature range of 300–700 K, stress–strain curves exhibit a dual-peak trend: the first peak arises from stress-induced transformations in the internal crystal structure, while the second peak corresponds to void nucleation and growth. At 900–1100 K, stress curves display a single-peak pattern, followed by rapid stress decline due to accelerated void coalescence. Structural evolution analysis reveals sequential phase transitions: initial BCC-to-FCC and -HCP transformations occur during deformation, followed by reversion to BCC and unidentified structures post-crack formation. Elevated temperatures enhance atomic mobility, increasing the proportion of disordered/unknown structures and accelerating material failure. Higher temperatures promote faster potential energy equilibration, primarily through accelerated void growth, which drives rapid energy dissipation.

The development of new therapeutic uses for existing drugs is important for the treatment of some diseases. Cephalosporin antibiotics stand as the most extensively utilized antibiotics in clinical practice, effectively combating bacterial infections. Here, we found that the antimicrobial drug ceftazidime strongly upregulates p27 protein levels by inhibiting p27 ubiquitination. The p27 protein is a classic negative regulator of the cell cycle. Next, we demonstrated that ceftazidime can impede the cell cycle from G1 to S phase, thus inhibiting cell proliferation. Furthermore, we found that ceftazidime promotes p27 expression and inhibits cell proliferation by reducing Skp2, which is a substrate recognition component of the Skp2-Cullin-F-box (SCF) ubiquitin ligase. Moreover, ceftazidime downregulates transcriptional expression of Skp2. Importantly, we demonstrated that ceftazidime inhibited the proliferation of tumor cells in vivo. These findings reveal ceftazidime-mediated inhibition of cell proliferation through the Skp2-p27 axis, and could provide a potential strategy for anti-tumor therapy.

CREB-binding protein (CBP) participates in numerous transcription events. However, cell-intrinsic inhibitors of CBP are poorly defined. Here, we found that cellular USP12 interacts with the HAT domain of CBP and inhibits CBP's acetyltransferase activity. Interestingly, USP12 positively regulates interferon (IFN) antiviral signaling independently of its deubiquitinase activity. Furthermore, we found that in IFN signaling USP12 translocates from the cytoplasm to the nucleus. The decrease in cytoplasmic USP12 facilitates CBP-induced acetylation and activation of IFN signaling proteins in the cytoplasm. Moreover, USP12 accumulation in the nucleus blocks CBP-induced acetylation of phosphorylated STAT1 (p-STAT1) and therefore inhibits the dephosphorylation effects of TCPTP on p-STAT1, which finally maintains nuclear p-STAT1 levels and IFN antiviral efficacy. USP12 nuclear translocation extends our understanding of the regulation of the strength of IFN antiviral signaling. Our study uncovers a cell-intrinsic regulation of CBP acetyltransferase activity and may provide potential strategies for IFN-based antiviral therapy.

Outbreaks of viral infections are a global health burden. Although type I interferon (IFN-I) exerts broad-spectrum antiviral effects, its antiviral efficacy in host cells is largely restricted by viruses. How the antiviral efficacy of IFN-I can be improved remains to be explored. Here, we identified the ADP-ribosyltransferase poly(ADP-ribose) polymerase family member 11 (PARP11) as a potent regulator of IFN-I antiviral efficacy. PARP11 does not restrict IFN-I production induced by vesicular stomatitis virus or Sendai virus but inhibits the strength of IFN-I-activated signalling. Mechanistically, PARP11 mono-ADP-ribosylates the ubiquitin E3 ligase β-transducin repeat-containing protein (β-TrCP). Mono-ADP-ribosylation of β-TrCP promotes IFNα/β receptor subunit 1 (IFNAR1) ubiquitination and degradation. Moreover, PARP11 expression is upregulated by virus infections, including vesicular stomatitis virus, herpes simplex virus-1 and influenza A virus, thus promoting ADP-ribosylation-mediated viral evasion. We further highlight the potential for repurposing clinical ADP-ribosylation inhibitors. We found that rucaparib can target PARP11 to stabilize IFNAR1 and therefore exhibits efficient enhancement of IFN-I signalling and the host antiviral response. Consequently, rucaparib renders mice more resistant to viral infection. Our study updates the understanding of how β-TrCP regulates its substrates and may provide a druggable target for improving IFN antiviral efficacy. The ADP-ribosyltransferase PARP11 promotes ubiquitination and degradation of the interferon type I (IFN-I) receptor IFNAR1 by mono-ADP-ribosylating the ubiquitin E3 ligase β-TrCP, thus suppressing the IFN-I-mediated antiviral responses both in vitro and in vivo.

DDX4, identified as a putative RNA helicase that modulates RNA secondary structure through RNA binding, is primarily acknowledged for its role in regulating mRNA translation within the germline. Nevertheless, the extent of DDX4’s involvement in the antiviral innate immune response remains largely unexplored. This study presents evidence of a previously unrecognized positive feedback loop between DDX4 and the antiviral response, suggesting that disruption of this loop may serve as a novel mechanism for viral evasion. Furthermore, our findings elucidate a positive regulatory mechanism by which the DDX4/USP7/SOCS1 axis mediates the antiviral activity of Type-I interferon, which provides new insight into strategies for improving the efficacy of IFN-based antiviral therapy.