Regulation of Cellular Antiviral Signaling by Modifications of Ubiquitin and Ubiquitin-like Molecules

The initiation of cellular antiviral signaling depends on host pattern-recognition receptors (PRRs)-mediated recognition of viral nucleic acids that are known as classical pathogen-associated molecular patterns (PAMPs). PRRs recruit adaptor proteins and kinases to activate transcription factors and epigenetic modifiers to regulate transcription of hundreds of genes, the products of which collaborate to elicit antiviral responses. In addition, PRRs-triggered signaling induces activation of various inflammasomes which leads to the release of IL-1β and inflammation. Recent studies have demonstrated that PRRs-triggered signaling is critically regulated by ubiquitin and ubiquitin-like molecules. In this review, we first summarize an updated understanding of cellular antiviral signaling and virus-induced activation of inflammasome and then focus on the regulation of key components by ubiquitin and ubiquitin-like molecules.

The role of mitochondrial DNA in the regulation of innate immune responses / 医学研究生学报

Mitochondria is the main production site of oxidative phosphorylation and ATP, and it is famous as energy factory of the cell.In addition, mitochondria also participates in the process of cellular proliferation, differentiation and apoptosis, and signal transduction.Recent studies have revealed that pathophysiological functions of mitochondria beyond traditional energetic metabolism in cells.Mitochondria-released DAMPs, particularly mtDNA, could activate innate immune responses by involving TLR9, NLRP3 and cGAS-STING signaling pathways.In addition to facilitating antibacterial immunity and regulating antiviral signaling, mounting evidences suggest that mtDNA contributes to inflammatory diseases following cellular damage and apoptosis.In addition to its well-appreciated roles in cellular metabolism and ATP production, mtDNA appears to function as a key member in the innate immune system.Therefore, we highlight the emerging roles of mtDNA in innate immunity.

Effect of high glucose or angiotensin Ⅱ on the expression of toll-like receptor 4 signal pathway,inflammatory and fibrotic factors in human tubular epithelial cells / 中华肾脏病杂志

Objective To investigate the effects of angiotensin Ⅱ (Ang Ⅱ) or high glucose on the toll-like receptor 4 (TLR4) expression,inflammatory cytokines and fibrotic factors in human tubular epithelial cells (HK-2),revealing the innate immune-related pathogenesis of diabetic nephropathy (DN) which may have clinical implications.Methods Three TLR4 siRNA sequences were designed and synthetized.After transfection,the most effective siRNA was selected to use for further expriments.The experiment consisted of 2 parts.Part 1:Cells were divided into three groups:normal-glucose group (NG,5.5mmol/L glucose),mannose group (M,5.5 mmol/L glucose + 19.5 mmol/L mannose),High-glucose group (HG,25 mmol/L glucose),preliminary validated the effects of high glucose and high osmotic pressure.Part 2:Cells were divided into seven groups:NG group,HG group,Ang Ⅱ group,Ang Ⅱ + negative group,HG+ negative group,Ang Ⅱ + siRNA group and HG+ siRNA group.Real time PCR was used to analyze the mRNA expression of TLR4,myeloid differentiation factor 88 (MyD88),heat shock protein 47 (HSP47).Western blotting was used to observe the protein expression of TLR4,MyD88,HSP47,NF-κB,type Ⅳ collagen (ColⅣ).ELISA was used to detect the expression of monocyte chemotactic protein-1 (MCP-1) and interleukin-6 (IL-6).Results Compared with NG group,TLR4,MyD88,HSP47 mRNA and TLR4,MyD88,NF-κB,ColⅣ,HSP47 protein were highly expressed under high glucose or Ang Ⅱconditions (P ＜ 0.01),and the expression levels of MCP-1 and IL-6 also increased significantly (P ＜ 0.01).Compared with HG or Ang Ⅱ group,the above indicators were obviously inhibited in the TLR4 siRNA groups (P＜0.01).Comparison between blank vector transfected groups and HG group as well as Ang Ⅱ group indicated no statistic significance (P ＞ 0.05).Conclusions Both Ang Ⅱ and high glucose stimulate TLR4 expression,which result in the up-regulation of inflammatory and fibrotic factors in HK-2.Specific target of TLR4 gene silencing can block the TLR4 pathway that is activated by high glucose and Ang Ⅱ,and thus reduce the inflammatory and fibtogenic factors' release.TLR4 signal is the common innate immune response pathway which induces the release of inflammatory and fibrotic factors in HK-2 under high glucose or high angiotension conditions.