Neurexin-3 in the paraventricular nucleus of the hypothalamus regulates body weight and glucose homeostasis independently of food intake.

Neurexin-3 (Nrxn3) has been genetically associated with obesity, but the underlying neural mechanisms remain poorly understood. This study aimed to investigate the role of Nrxn3 in the paraventricular nucleus of the hypothalamus (PVN) in regulating energy balance and glucose homeostasis. We found that Nrxn3 expression in the PVN was upregulated in response to metabolic stressors, including cold exposure and fasting. Using Cre-loxP technology, we selectively ablated Nrxn3 in CaMKIIα-expressing neurons of the PVN in male mice. This genetic manipulation resulted in marked weight gain attributable to increased adiposity and impaired glucose tolerance, without affecting food intake. Our findings identify PVN CaMKIIα-expressing neurons as a critical locus where Nrxn3 modulates energy balance by regulating adipogenesis and glucose metabolism, independently of appetite. These results reveal a novel neural mechanism potentially linking Nrxn3 dysfunction to obesity pathogenesis, suggesting that targeting PVN Nrxn3-dependent neural pathways may inform new therapeutic approaches for obesity prevention and treatment.

Selenium-Doped Seeded Growth of Truncated Octahedral Gold Nanocrystals with Surface Concavities for Surface-Enhanced Raman Spectroscopy.

Concave nanocrystals stand out as a testament to the importance of the nanoscale morphology in dictating the functional properties of materials. In this report, we introduce a facile synthesis method for producing gold (Au) nanocrystals with a truncated octahedral morphology that features surface concavities (Au CNTOs). The incorporation of selenium (Se) doping into the truncated octahedral Au seeds was essential for their enlargement and the formation of concave structures. By simply adjusting the quantity of seeds, we could control the size of the nanocrystals while maintaining their distinctive morphology and surface concavity. The formation mechanism suggests that Se doping likely passivates the side faces, thereby slowing growth and promoting atomic deposition at the edges and corners. The resulting Se-doped Au CNTOs exhibited strong localized surface plasmon resonance (LSPR) absorptions in the visible spectrum and the SERS performance of their assemblies was demonstrated through crystal violet detection, reaching enhancement factors around 105. This study presents an innovative approach to synthesizing concave Au nanocrystals through the incorporation of selenium during a seeded growth process, offering insights into the strategic design of plasmonic nanostructures.

CTHRC1 modulates cell proliferation and invasion in hepatocellular carcinoma by DNA methylation.

BACKGROUND: Collagen triple helix repeat containing-1 (CTHRC1), an extracellular matrix protein, is highly expressed in hepatocellular carcinoma (HCC) and linked to poor prognosis. Nevertheless, the precise mechanism of CTHRC1 in HCC is unclear. METHODS: Agena MassARRAY® Methylation Analysis assessed the methylation level of CTHRC1 in the promoter region. Functional assays were conducted to investigate the effects of CTHRC1 knockdown in Hep3B2.1 cells. RNA sequencing identified differentially expressed genes and lncRNAs associated with angiogenesis after CTHRC1 knockdown. Furthermore, differential alternative splicing (AS) and gene fusion events were analyzed using rMATS and Arriba. RESULTS: In HCC cell lines, CTHRC1 was highly expressed and associated with hypomethylation. Downregulation of CTHRC1 inhibited Hep3B2.1 cell proliferation, migration, and invasion, blocked cells in the G1/S phase, and promoted apoptosis. We obtained 34 mRNAs and 7 lncRNAs differentially expressed between the NC and CTHRC1 inhibitor groups. Additionally, we found 4 angiogenesis-related mRNAs and lncRNAs significantly correlated with CTHRC1. RT-qPCR results showed that knockdown of CTHRC1 in Hep3B2.1 cells resulted in significantly aberrant expression of CXCL6, LINC02127, and AC020978.8. Moreover, the role of CTHRC1 in HCC development may be associated with events, like 12 AS events and 5 pairs of fusion genes. CONCLUSIONS: High expressed CTHRC1 is associated with hypomethylation and may promote HCC development, involving events like angiogenesis, alternative splicing, and gene fusion.

Targeting myeloid-derived suppressor cells promotes antiparasitic T-cell immunity and enhances the efficacy of PD-1 blockade (15 words).

Immune exhaustion corresponds to a loss of effector function of T cells that associates with cancer or chronic infection. Here, our objective was to decipher the mechanisms involved in the immune suppression of myeloid-derived suppressor cells (MDSCs) and to explore the potential to target these cells for immunotherapy to enhance checkpoint blockade efficacy in a chronic parasite infection. We demonstrated that programmed cell-death-1 (PD-1) expression was significantly upregulated and associated with T-cell dysfunction in advanced alveolar echinococcosis (AE) patients and in Echinococcus multilocularis-infected mice. PD-1 blockade ex vivo failed to reverse AE patients' peripheral blood T-cell dysfunction. PD-1/PD-L1 blockade or PD-1 deficiency had no significant effects on metacestode in mouse model. This was due to the inhibitory capacities of immunosuppressive granulocytic MDSCs (G-MDSCs), especially in the liver surrounding the parasite pseudotumor. MDSCs suppressed T-cell function in vitro in an indoleamine 2, 3 dioxygenase 1 (IDO1)-dependent manner. Although depleting MDSCs alone restored T-cell effector functions and led to some limitation of disease progression in E. multilocularis-infected mice, combination with PD-1 blockade was better to induce antiparasitic efficacy. Our findings provide preclinical evidence in support of targeting MDSC or combining such an approach with checkpoint blockade in patients with advanced AE. (200 words).

Photoredox coupling of carbon dioxide reduction with tetracycline oxidation using excited-state bismuth and cobalt dual sites over cobalt-tailored bismuth oxychloride.

Photocatalytic carbon dioxide (CO2) conversion and simultaneous pollutant oxidation in a single system are promising approaches to mitigate energy and environmental challenges. However, the limited availability of active photocatalyst sites led to slow reaction kinetics and poor selectivity. Current research has predominantly focused on ground-state reactive sites of semiconductors, with less emphasis on active sites in their excited states. Therefore, gaining insights into the active sites in the excited state of semiconductors could provide a significant breakthrough in understanding the photocatalytic reaction mechanism. In this study, cobalt-doped bismuth oxychloride nanosheets containing abundant oxygen vacancies (OVs) were used as a model to investigate the active sites in excited states. These nanosheets were used to integrate CO2 reduction with tetracycline (TC) oxidation. Combining theoretical calculations with in situ characterizations revealed that under excited-state conditions photogenerated electrons transfer from cobalt (Co) dopants to OVs and subsequently to bismuth (Bi) atoms, forming Bi(3-x)+ sites enriched with excited electrons. These excited-electron-rich Bi(3-x)+ sites and electron-deficient Co sites contribute to CO2 reduction and TC oxidation, respectively. This study provides a comprehensive understanding of active sites in the excited state in doped semiconductors at the atomic level, reinforcing their potential for synergistic CO2 reduction and pollutant degradation.

USP5 Promotes Ripretinib Resistance in Gastrointestinal Stromal Tumors by MDH2 Deubiquition.

Ripretinib, a broad-spectrum inhibitor of the KIT and PDGFRA receptor tyrosine kinases, is designated as a fourth-line treatment for gastrointestinal stromal tumor (GIST). It is tailored for patients resistant to imatinib, sunitinib, and regorafenib. As its increasing use, instances of resistance to ripretinib are becoming more frequent. Unfortunately, there are currently no scientifically mature treatment options available for patients resistant to ripretinib. Posttranslational modifications (PTMs) such as ubiquitination, in conjunction with its interplay with other modifications, play a collective role in regulating tumor initiation and progression. However, the specific association between ubiquitination and ripretinib resistance is not reported. Through proteome-ubiquitinome sequencing, increased levels of the USP5 protein and decreased ubiquitination in ripretinib-resistant GISTs are detected. Subsequent examination of the mass spectrometry findings validated the interaction through which TRIM21 governs USP5 expression via ubiquitination, and USP5 regulates MDH2 expression through deubiquitination, consequently fostering ripretinib resistance in GIST. Moreover, ZDHHC18 can palmitoylate MDH2, preventing its ubiquitination and further increasing its protein stability. The research underscores the correlation between posttranslational modifications, specifically ubiquitination, and drug resistance, emphasizing the potential of targeting the USP5-MDH2 axis to counteract ripretinib resistance in GIST.

Hepatocyte-derived FGL1 accelerates liver metastasis and tumor growth by inhibiting CD8+ T and NK cells.

Fibrinogen-like protein 1 (FGL1) contributes to the proliferation and metabolism of hepatocytes; however, as a major ligand of the immune checkpoint, its role in the liver regional immune microenvironment is poorly understood. Hepatocytes specifically and highly expressed FGL1 under normal physiological conditions. Increases in hepatic CD8+ T and NK cell numbers and functions were found in Fgl1-deficient (Fgl1-/-) mice, but not in the spleen or lymph node, similar to findings in anti-FGL1 mAb-treated wild-type mice. Furthermore, Fgl1 deficiency or anti-FGL1 mAb blockade restrained liver metastasis and slowed the growth of orthotopic tumors, with significantly prolonged survival of tumor-bearing mice. Tumor-infiltrating hepatic CD8+ T and NK cells upregulated the expression of lymphocyte activation gene-3 (LAG-3) and exhibited stronger antitumor activities after anti-FGL1 treatment. The antitumor efficacy of FGL1 blockade depended on cytotoxic T lymphocytes and NK cells, demonstrated by using a cell-deficient mouse model and cell transfer in vivo. In vitro, FGL1 directly inhibited hepatic T and NK cells related to the receptor LAG-3. In conclusion, hepatocyte-derived FGL1 played critical immunoregulatory roles in the liver and contributed to liver metastasis and tumor growth by inhibiting CD8+ T and NK cell functions via the receptor LAG-3, providing a new strategy for liver cancer immunotherapy.

The E3 ubiquitin ligase FBXO38 maintains the antitumor function of natural killer cells by sustaining IL-15R signaling.

Natural killer (NK) cells are the main innate antitumor effector cells but their function is often constrained in the tumor microenvironment (TME). It has been reported that the E3 ligase FBXO38 accelerates PD-1 degradation in tumor-infiltrating T cells to unleash their cytotoxic function. In this study, we found that the transcriptional levels of FBXO38 in intratumoral NK cells of cancer patients and tumor-bearing mice were significantly lower than in peritumoral NK cells. Conditional knock-out (cKO) of FBXO38 in NK cells accelerated tumor growth and increased tumor metastasis. FBXO38 deficiency resulted in impaired proliferation and survival of tumor-infiltrating NK (TINK) cells. Mechanistically, FBXO38 deficiency enhanced TGF-ß signaling, including elevating expression of Smad2 and Smad3, which suppressed expression of the transcription factor Eomes and further reduced expression of surface IL-15Rß and IL-15Rγc on NK cells. Consequently, FBXO38 deficiency led to TINK cell hyporesponsiveness to IL-15. Consistent with these observations, FBXO38 mRNA expression was positively correlated with the proliferation of TINK cells in multiple human tumors. To study the therapeutic potential of FBXO38, mice bearing human tumors were treated with FBXO38 overexpressed human primary NK cells and showed a significant reduction in tumor size and prolonged survival. In conclusion, our results suggest that FBXO38 sustains NK-cell expansion and survival to promote antitumor immunity, and have potential therapeutic implications as they suggest FBXO38 could be harnessed to enhance NK cell-based cancer immunotherapy.

Enhancing biohydrogen production from xylose at low temperature (20 °C) using natural FeS2 Ore: Thermodynamic analysis and mechanistic insights.

This study investigates the efficacy of pyrite in enhancing biohydrogen production from xylose at low temperature (20 °C). Higher hydrogen yield rates (Rm) and reduced lag time (λ) were achieved across initial xylose concentrations ranging from 2-10 g/L. At an optimal xylose concentration of 5 g/L, pyrite reduced λ by 2.5 h and increased Rm from 1.3 to 2.7 mL h-1. These improvements are attributed to pyrite's ability to enhance the secretion of extracellular polymeric substance and flavins, facilitate NADH and NAD+ generation and transition, and favor biohydrogen production. Thermodynamic analyses and Gibbs free energy calculations further elucidated pyrite's role in the full reaction process and rate-limiting steps at low temperature. This study offers valuable insights into improving the efficiency of biohydrogen production at low temperature, with significant implications for energy conservation.

m6A modification of lncRNA ABHD11-AS1 promotes colorectal cancer progression and inhibits ferroptosis through TRIM21/IGF2BP2/ FOXM1 positive feedback loop.

Long non-coding RNA (lncRNA) is closely related to a variety of human cancers, which may provide huge potential biomarkers for cancer diagnosis and treatment. However, the aberrant expression of most lncRNAs in colorectal cancer (CRC) remains elusive. This study aims to explore the clinical significance and potential mechanism of lncRNA ABHD11 antisense RNA 1 (ABHD11-AS1) in the colorectal cancer. Here, we demonstrated that lncRNA ABHD11-AS1 is high-expressed in colorectal cancer (CRC) patients, and strongly related with poor prognosis. Functionally, ABHD11-AS1 suppresses ferroptosis and promotes proliferation and migration in CRC both in vitro and in vivo. Mechanically, lncRNA ABHD11-AS1 interacted with insulin-like growing factor 2 mRNA-binding protein 2 (IGF2BP2) to enhance FOXM1 stability, forming an ABHD11-AS1/FOXM1 positive feedback loop. E3 ligase tripartite motif containing 21 (TRIM21) promotes the degradation of IGF2BP2 via the K48-ubiquitin-lysosome pathway and ABHD11-AS1 promotes the interaction between IGF2BP2 and TRIM21 as scaffold platform. Furthermore, N6 -adenosine-methyltransferase-like 3 (METTL3) upregulated the stabilization of ABHD11-AS1 through the m6A reader IGF2BP2. Our study highlights ABHD11-AS1 as a significant regulator in CRC and it may become a potential target in future CRC treatment.

Acute toxicity of binary mixtures for quorum sensing inhibitors and sulfonamides against Aliivibrio fischeri: QSAR investigations and joint toxic actions.

Quorum sensing inhibitors (QSIs), as a kind of ideal antibiotic substitutes, have been recommended to be used in combination with traditional antibiotics in medical and aquaculture fields. Due to the co-existence of QSIs and antibiotics in environmental media, it is necessary to evaluate their joint risk. However, there is little information about the acute toxicity of mixtures for QSIs and antibiotics. In this study, 10 QSIs and 3 sulfonamides (SAs, as the representatives for traditional antibiotics) were selected as the test chemicals, and their acute toxic effects were determined using the bioluminescence of Aliivibrio fischeri (A. fischeri) as the endpoint. The results indicated that SAs and QSIs all induced S-shaped dose-responses in A. fischeri bioluminescence. Furthermore, SAs possessed greater acute toxicity than QSIs, and luciferase (Luc) might be the target protein of test chemicals. Based on the median effective concentration (EC50) for each test chemical, QSI-SA mixtures were designed according to equitoxic (EC50(QSI):EC50(SA) = 1:1) and non-equitoxic ratios (EC50(QSI):EC50(SA) = 1:10, 1:5, 1:0.2, and 1:0.1). It could be observed that with the increase of QSI proportion, the acute toxicity of QSI-SA mixtures enhanced while the corresponding TU values decreased. Furthermore, QSIs contributed more to the acute toxicity of test binary mixtures. The joint toxic actions of QSIs and SAs were synergism for 23 mixtures, antagonism for 12 mixtures, and addition for 1 mixture. Quantitative structure-activity relationship (QSAR) models for the acute toxicity QSIs, SAs, and their binary mixtures were then constructed based on the lowest CDOCKER interaction energy (Ebind-Luc) between Luc and each chemical and the component proportion in the mixture. These models exhibited good robustness and predictive ability in evaluating the toxicity data and joint toxic actions of QSIs and SAs. This study provides reference data and applicable QSAR models for the environmental risk assessment of QSIs, and gives a new perspective for exploring the joint effects of QSI-antibiotic mixtures.

Enhancing biohydrogen production from xylose through natural FeS2 ore: Mechanistic insights.

In this study, we investigated the advantages of utilizing natural FeS2 ore in the context of dark fermentative hydrogen production within a fermentation system employing heat-treated anaerobic granular sludge with xylose as the carbon source. The results demonstrated a significant improvement in both hydrogen production and the maximum rate, with increases of 2.58 and 4.2 times, respectively. Moreover, the presence of FeS2 ore led to a reduction in lag time by more than 2-3 h. The enhanced biohydrogen production performance was attributed to factors such as the intracellular NADH/NAD+ ratio, redox-active components of extracellular polymeric substances, secreted flavins, as well as the presence of hydrogenase and nitrogenase. Furthermore, the FeS2 ore served as a direct electron donor and acceptor during biohydrogen production. This study shed light on the underlying mechanisms contributing to the improved performance of biohydrogen production from xylose during dark fermentation through the supplementation of natural FeS2 ore.

Genome editing of FTR42 improves zebrafish survival against virus infection by enhancing IFN immunity.

The development of CRISPR-Cas9 technology introduces an efficient tool for precise engineering of fish genomes. With a short reproduction cycle, zebrafish infection mode can be referenced as antiviral breeding researches in aquaculture fish. Previously we identified a crucian carp-specific gene ftrca1 as an inhibitor of interferon response in vitro. Here, we demonstrate that genome editing of zebrafish ftr42, a homolog of ftrca1, generates a zebrafish mutant (ftr42lof/lof) with an improved resistance to SVCV infection. Zebrafish ftr42 acts as a virus-induced E3 ligase and downregulates IFN antiviral response by facilitating TBK1 protein degradation and also IRF7 mRNA decay. Genome editing results in loss of function of zebrafish ftr42, which enables zebrafish to have enhanced interferon response, thus improving zebrafish survival against virus infection. Our results suggest that fine-tuning fish IFN innate immunity through genome editing of negative regulators can genetically improve viral resistance in fish.

Blockade of CD300A enhances the ability of human NK cells to lyse hematologic malignancies.

OBJECTIVE: The human cluster of differentiation (CD)300A, a type-I transmembrane protein with immunoreceptor tyrosine-based inhibitory motifs, was investigated as a potential immune checkpoint for human natural killer (NK) cells targeting hematologic malignancies (HMs). METHODS: We implemented a stimulation system involving the CD300A ligand, phosphatidylserine (PS), exposed to the outer surface of malignant cells. Additionally, we utilized CD300A overexpression, a CD300A blocking system, and a xenotransplantation model to evaluate the impact of CD300A on NK cell efficacy against HMs in in vitro and in vivo settings. Furthermore, we explored the association between CD300A and HM progression in patients. RESULTS: Our findings indicated that PS hampers the function of NK cells. Increased CD300A expression inhibited HM lysis by NK cells. CD300A overexpression shortened the survival of HM-xenografted mice by impairing transplanted NK cells. Blocking PS-CD300A signals with antibodies significantly amplified the expression of lysis function-related proteins and effector cytokines in NK cells, thereby augmenting the ability to lyse HMs. Clinically, heightened CD300A expression correlated with shorter survival and an "exhausted" phenotype of intratumoral NK cells in patients with HMs or solid tumors. CONCLUSIONS: These results propose CD300A as a potential target for invigorating NK cell-based treatments against HMs.

Single-Shot Readout of a Solid-State Electron Spin Qutrit.

Quantum systems usually feature a rich multilevel structure with promising resources for developing superior quantum technologies compared with their binary counterpart. Single-shot readout of these high-dimensional quantum systems is essential for exploiting their potential. Although there have been various high-spin systems, the single-shot readout of the overall state of high-spin systems remains a challenging issue. Here we demonstrate a reliable single-shot readout of spin qutrit state in a low-temperature solid-state system utilizing a binary readout scheme. We achieve a single-shot readout of an electron spin qutrit associated with a single nitrogen-vacancy center in diamond with an average fidelity of 87.80%. We use this spin qutrit system to verify quantum contextuality, a fundamental test of quantum mechanics. We observe a violation of the noncontextual hidden variable inequality with the developed single-shot readout in contrast to the conventional binary readout. These results pave the way for developing quantum information processing based on spin qutrits.

Drivers of desert plant beta diversity on the Qinghai-Tibet plateau.

The desert ecosystem of the Qinghai-Tibet Plateau (QTP) is an important component of China's desert ecosystem. Studying the mechanisms shaping the taxonomic, phylogenetic, and functional beta diversity of plant communities in the QTP desert will help us to promote scientific conservation and management of the region's biodiversity. This study investigated the effects of environmental (including altitude, climate factors, and soil factors) and geographic distances on three facets of beta diversity as well as their turnover and nestedness components based on field survey data. The results showed that turnover components dominate the three facets of beta diversity. However, the turnover contributions to phylogenetic and functional beta diversity were lower than for taxonomic beta diversity. Environmental distance had a greater influence than geographic distance, with the former uniquely explaining 15.2%-22.8% of beta diversity and the latter explaining only 1.7%-2.4%. Additionally, the explanatory power of different factors for beta diversity differed between herbs and shrubs, with environmental distance being more important for the latter. Distance-based redundancy analysis suggested that soil total potassium content had a substantial impact on the beta diversity of three dimensions, with mean temperature of the coldest month and soil total phosphorus content having a substantial impact on taxonomic and functional beta diversity as well. Our results support that environmental sorting plays a predominant role in shaping plant community composition across QTP desert ecosystems. To maintain the plant diversity of this region, it is crucial to prioritize the conservation of its diverse environmental conditions and actively mitigate its degradation by anthropogenic pressures.

DEAD-box RNA helicase 21 interacts with porcine circovirus type 2 Cap protein and facilitates viral replication.

Porcine circovirus type 2 (PCV2) is the etiological agent of PCV2-associated diseases that pose a serious threat to the swine industry. PCV2 capsid (Cap) protein has been shown to interact with DEAD-box RNA helicase 21 (DDX21), an important protein that regulates RNA virus replication. However, whether the interaction between DDX21 and the PCV2 Cap regulates PCV2 replication remains unclear. Herein, by using western blotting, interaction assays, and knockdown analysis, we found that PCV2 infection induced the cytoplasmic relocation of DDX21 from the nucleolus in cultured PK-15 cells. Moreover, the nuclear localization signal (NLS) of PCV2 Cap interacted directly with DDX21. The NLS of PCV2 Cap and 763GSRSNRFQNK772 residues at the C-terminal domain (CTD) of DDX21 were essential for the dual interaction. Upon shRNA-mediated DDX21 depletion in PK-15 cells, we observed impaired PCV2 replication via a lentivirus-delivered system, as evidenced by decreased levels of viral protein expression and virus production. In contrast, the replication of PCV2 increased in transiently DDX21-overexpressing cells. Our results indicate that DDX21 interacts with PCV2 Cap and plays a crucial role in virus replication. These results provide a reference for developing novel potential targets for prevention and control of PCV2 infection.

Corrigendum: Bispecific NK-cell engager targeting BCMA elicits stronger antitumor effects and produces less proinflammatory cytokines than T-cell engager.

[This corrects the article DOI: 10.3389/fimmu.2023.1113303.].

Oxygen vacancies synergistic cobalt phosphide electron bridge modulated bismuth oxychloride/carbon nitride Z-scheme junction for efficient carbon dioxide reduction coupled with tetracycline oxidation.

Although great progress has been made with respect to electron bridges, the electron mobility of the state-of-the-art electron bridges is far from satisfactory because of weak electrical conductivity. To overcome the above issue, cobalt phosphide (CoP), as a model electron bridge, was modified by superficial oxygen vacancies (OVs) and embedded into a defective bismuth oxychloride/carbon nitride (BiO1-xCl/g-C3N4) Z-scheme heterojunction to obtain atomic-level insights into the effect of surface OVs on CoP electron bridges. Compared to BiO1-xCl/g-C3N4 and bismuth oxychloride/cobalt phosphide/carbon nitride (BiOCl/CoP/g-C3N4) composites, the defective bismuth oxychloride/cobalt phosphide/carbon nitride (BiO1-xCl/CoP/g-C3N4) heterojunction exhibited remarkable photocatalytic redox performance, indicating that the surface OVs-assisted CoP electron bridge effectively boosted electrical conductivity and yielded ultrafast electron transfer rates. The theoretical and experimental results demonstrate that the surface OVs play a critical role in improving the electrical conductivity of the CoP electron bridge, thereby accelerating electron mobility. This research provides insights into interfacial OVs-modified transition metal phosphide (TMP) electron bridges and their potential application in heterojunctions for energy crisis mitigation and environmental remediation.

A zebrafish NLRX1 isoform downregulates fish IFN responses by targeting the adaptor STING.

In mammals, NLRX1 is a unique member of the nucleotide-binding domain and leucine-rich repeat (NLR) family showing an ability to negatively regulate IFN antiviral immunity. Intron-containing genes, including NLRX1, have more than one transcript due to alternative splicing; however, little is known about the function of its splicing variants. Here, we identified a transcript variant of NLRX1 in zebrafish (Danio rerio), termed NLRX1-tv4, as a negative regulator of fish IFN response. Zebrafish NLRX1-tv4 was slightly induced by viral infection, with an expression pattern similar to the full-length NLRX1. Despite the lack of an N-terminal domain that exists in the full-length NLRX1, overexpression of NLRX1-tv4 still impaired fish IFN antiviral response and promoted viral replication in fish cells, similar to the full-length NLRX1. Mechanistically, NLRX1-tv4 targeted STING for proteasome-dependent protein degradation by recruiting an E3 ubiquitin ligase RNF5 to drive the K48-linked ubiquitination, eventually downregulating the IFN antiviral response. Mapping of NLRX1-tv4 domains showed that its N-terminal and C-terminal regions exhibited a similar potential to inhibit STING-mediated IFN antiviral response. Our findings reveal that like the full-length NLRX1, zebrafish NLRX-tv4 functions as an inhibitor to shape fish IFN antiviral response.IMPORTANCEIn this study, we demonstrate that a transcript variant of zebrafish NLRX1, termed NLRX1-tv4, downregulates fish IFN response and promotes virus replication by targeting STING for protein degradation and impairing the interaction of STING and TBK1 and that its N- and C-terminus exhibit a similar inhibitory potential. Our results are helpful in clarifying the current contradictory understanding of structure and function of vertebrate NLRX1s.