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To effectively protect the host from viral infection while avoiding excessive immunopathology, the innate immune response must be tightly controlled. However, the precise regulation of antiviral innate immunity and the underlying mechanisms remain unclear. Here, we find that sirtuin3 (SIRT3) interacts with mitochondrial antiviral signaling protein (MAVS) to catalyze MAVS deacetylation at lysine residue 7 (K7), which promotes MAVS aggregation, as well as TANK-binding kinase I and IRF3 phosphorylation, resulting in increased MAVS activation and enhanced type I interferon signaling. Consistent with these findings, loss of Sirt3 in mice and zebrafish renders them more susceptible to viral infection compared to their wild-type (WT) siblings. However, Sirt3 and Sirt5 double-deficient mice exhibit the same viral susceptibility as their WT littermates, suggesting that loss of Sirt5 in Sirt3-deficient mice may counteract the increased viral susceptibility displayed in Sirt3-deficient mice. Thus, we not only demonstrate that SIRT3 positively regulates antiviral immunity in vitro and in vivo, likely via MAVS, but also uncover a previously unrecognized mechanism by which SIRT3 acts as an accelerator and SIRT5 as a brake to orchestrate antiviral innate immunity. [ABSTRACT FROM AUTHOR]

The hypoxia-inducible factor (HIF)-mediated hypoxia signaling pathway influences oxygen homeostasis in aerobic organisms. This pathway is regulated by several other pathways. Elucidation of its regulation and the underlying mechanisms may provide insights into the strategies of adaptation and tolerance of organisms to hypoxia. In this study, we found that loss of ubiquitin-specific protease 3 (usp3) in zebrafish promotes hypoxia tolerance. Zebrafish usp3 specifically binds to hif-1αa and induces its proteasomal degradation, which is dependent on its deubiquitinase activity. This process leads to the suppression of hypoxia signaling under hypoxia. In addition, usp3 catalyzes the deubiquitination of K63-polyubiquitinated hif-1αa. Endogenous evidence indicated that mammalian USP3 behaves like zebrafish usp3 in regulating the activity of HIF-1α. These findings revealed a novel role for usp3 in influencing hypoxia signaling and showed that usp3-mediated HIF-1α degradation impairs hypoxia signaling, leading to a decrease in hypoxia tolerance. [ABSTRACT FROM AUTHOR]

The cytosolic RNA and DNA sensors initiate type I interferon signaling when binding to RNA or DNA. To effectively protect the host against virus infection and concomitantly avoid excessive interferonopathy at resting states, these sensors must be tightly regulated. However, the key molecular mechanisms regulating these sensors’ activation remain elusive. Here, we identify PRMT3, a type I protein arginine methyltransferase, as a negative regulator of cytosolic RNA and DNA sensors. PRMT3 interacts with RIG-I, MDA5, and cGAS and catalyzes asymmetric dimethylation of R730 on RIG-I, R822 on MDA5, and R111 on cGAS. These modifications reduce RNA-binding ability of RIG-I and MDA5 as well as DNA-binding ability and oligomerization of cGAS, leading to the inhibition of downstream type I interferon production. Furthermore, mice with loss of one copy of Prmt3 or in vivo treatment of the PRMT3 inhibitor, SGC707, are more resistant to RNA and DNA virus infection. Our findings reveal an essential role of PRMT3 in the regulation of antiviral innate immunity and give insights into the molecular regulation of cytosolic RNA and DNA sensors’ activation. [ABSTRACT FROM AUTHOR]

The hypoxia-inducible factors 1α and 2α (HIF1α and HIF2α) are master regulators of the cellular response to O2. In addition to HIF1α and HIF2α, HIF3α is another identified member of the HIFα family. Even though the question of whether some HIF3α isoforms have transcriptional activity or repressive activity is still under debate, it is evident that the full length of HIF3α acts as a transcription factor. However, its function in hypoxia signaling is largely unknown. Here, we show that loss of hif3a in zebrafish reduced hypoxia tolerance. Further assays indicated that erythrocyte number was decreased because red blood cell maturation was impeded by hif3a disruption. We found that gata1 expression was downregulated in hif3a null zebrafish, as were several hematopoietic marker genes, including alas2, band3, hbae1, hbae3 and hbbe1. Hif3α recognized the hypoxia response element located in the promoter of gata1 and directly bound to the promoter to transactivate gata1 expression. Our results suggested that hif3a facilities hypoxia tolerance by modulating erythropoiesis via gata1 regulation. [ABSTRACT FROM AUTHOR]

Niemann-Pick type C disease (NPC) is a rare human disease, with limited effective treatment options. Most cases of NPC disease are associated with inactivating mutations of the NPC1 gene. However, cellular and molecular mechanisms responsible for the NPC1 pathogenesis remain poorly defined. This is partly due to the lack of a suitable animal model to monitor the disease progression. In this study, we used CRISPR to construct an NPC1-/- zebrafish model, which faithfully reproduced the cardinal pathological features of this disease. In contrast to the wild type (WT), the deletion of NPC1 alone caused significant hepatosplenomegaly, ataxia, Purkinje cell death, increased lipid storage, infertility and reduced body length and life span. Most of the NPC1-/- zebrafish died within the first month post fertilization, while the remaining specimens developed slower than the WT and died before reaching 8 months of age. Filipin-stained hepatocytes of the NPC1-/- zebrafish were clear, indicating abnormal accumulation of unesterified cholesterol. Lipid profiling showed a significant difference between NPC1-/- and WT zebrafish. An obvious accumulation of seven sphingolipids was detected in livers of NPC1-/- zebrafish. In summary, our results provide a valuable model system that could identify promising therapeutic targets and treatments for the NPC disease. [ABSTRACT FROM AUTHOR]

CXCR3, predominately expressed on memory/activated T cells, is a receptor for both interferon-γ inducible protein-10/CXC ligand 10 (CXCL10) and monokine induced by interferon-γ/CXCL9. We reported here that CXCR3 was highly up-regulated on infiltrating eosinophils in Schistosoma japonicum egg-induced granuloma in the mouse liver. It was also highly and functionally up-regulated on peritoneal exudate eosinophils in mice infected with S. japonicum. The phenomena were demonstrated at protein and mRNA levels using immunohisto- and immunocytochemistry evaluation of biopsy, flow cytometry and real-time quantitative reverse transcriptase–polymerase chain reaction technique, and verified by Northern blotting and chemotaxis assay in vitro. We also found that CCR3 expression on the infiltrating and peritoneal exudate cells was significantly decreased, CXCR4 expression was unchanged during the 42-day period of infection. We screened mRNA expression levels of the all known chemokine receptors in purified peritoneal exudate eosinophils and liver granuloma dominated by eosinophils. CXCR3 was highly and functionally up-regulated on peritoneal exudate eosinophils in mice infected with S. japonicum, meanwhile CCR3 was significantly and functionally down-regulated in these cells. The findings could lead to a better understanding of the chemokine receptor expression pattern of eosinophils at inflamed tissue sites caused by parasites. These could be also crucial for establishing a therapeutic strategy for eosinophilic inflammation via intervention in chemokine actions. [ABSTRACT FROM AUTHOR]