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Aberrant N-glycosylation has been implicated in viral diseases. Alpha-(1,6)-fucosyltransferase (FUT8) is the sole enzyme responsible for core fucosylation of N-glycans during glycoprotein biosynthesis. Here we find that multiple viral envelope proteins, including Hepatitis C Virus (HCV)-E2, Vesicular stomatitis virus (VSV)-G, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-Spike and human immunodeficiency virus (HIV)-gp120, enhance FUT8 expression and core fucosylation. HCV-E2 manipulates host transcription factor SNAIL to induce FUT8 expression through EGFR-AKT-SNAIL activation. The aberrant increased-FUT8 expression promotes TRIM40-mediated RIG-I K48-ubiquitination and suppresses the antiviral interferon (IFN)-I response through core fucosylated-EGFR-JAK1-STAT3-RIG-I signaling. FUT8 inhibitor 2FF, N-glycosylation site-specific mutation (Q352AT) of EGFR, and tissue-targeted Fut8 silencing significantly increase antiviral IFN-I responses and suppress RNA viral replication, suggesting that core fucosylation mediated by FUT8 is critical for antiviral innate immunity. These findings reveal an immune evasion mechanism in which virus-induced FUT8 suppresses endogenous RIG-I-mediated antiviral defenses by enhancing core fucosylated EGFR-mediated activation. Alpha-(1,6)-fucosyltransferase (FUT8) is the sole enzyme responsible for core fucosylation of N-glycans during glycoprotein biosynthesis. Here the authors show that HCV envelope protein E2 enhances FUT8 expression through the EGFR-AKT-SNAIL axis, which subsequently promotes RIG-I K48-ubiquitination and dampens the antiviral IFN-I response through core fucosylated-EGFR-JAK1-STAT3-RIG-I pathway.

Mycobacterium tuberculosis (Mtb) , as an important intracellular pathogen, can invade and survive in macrophages and is capable of escaping the clearance of immune system. Despite decades of research efforts, the precise mechanism of immune escape and the virulence factors encoded by Mtb involved remain to be explored. Mtb -specific genomic regions of deletion (RD)-encoded proteins and PE/PPE family proteins have been implicated in immune evasion. Here, we screened more than forty RD-encoded proteins which might be involved in facilitating bacterial survival in macrophages, and found that a Mtb PPE68/Rv3873 protein, encoded by Mtb -RD1, is essential for efficient Mtb intracellular survival in macrophages. In terms of mechanism, we found that the ubiquitin ligase (E3) Makorin Ring Finger Protein 1 (MKRN1) of macrophage interacted with PPE68 and promoted the attachment of lysine (K)-63-linked ubiquitin chains to the K166 site of PPE68. K63-ubiquitination of PPE68 further bound src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1) to suppress K63-linked polyubiquitin chains of tumor necrosis factor receptor-associated factor 6 (TRAF6), and then remarkably suppressed TRAF6-driven NF-κB and AP-1 signaling and TNF-α, IL-6 and NO production. We demonstrate that the K63-linked ubiquitination of PPE68 by MKRN1 contributed to the PPE68-mediated mycobacterial immune escape. Our finding identifies a previously unrecognized mechanism by which host MKRN1-mediated-ubiquitination of mycobacterial PPE protein suppresses innate immune responses. Disturbing the interaction between host MKRN1 ubiquitin system and mycobacterial PPE protein might be a potential therapeutic target for tuberculosis.

Pyroptosis is an important inflammatory form of cell death and ( ) chronic infection triggers excessive inflammatory pyroptosis of macrophages. Our previous research has confirmed that a small compound pyrvinium pamoate (PP) could inhibit inflammatory pathological changes and mycobacterial burden in -infected mice, but the potential mechanism of PP for inhibiting -induced inflammation remains unexplored. The effects of PP on the NLRP3-ASC-Casp1 inflammasome assembly and activation, gasdermin D (GSDMD) mediated pyroptosis and inflammatory cytokines expression were assessed in human THP-1-derived macrophages after H37Rv/H37Ra/ ( ) infection or LPS treatment by Transcriptome sequencing, RT-qPCR, Co-immunoprecipitation and Western Blot (WB) analysis. The lactate dehydrogenase (LDH) release assay was used to evaluate the CC50 of PP in -infected THP-1 cells. We found that / infection and LPS treatment significantly activate NLRP3-ASC-Casp1 inflammasome activation, GSDMD-mediated pyroptosis and inflammatory cytokines (IL-1β and IL-18) expression in macrophages, whereas PP could suppress these inflammatory effects in a dose dependent manner. Regarding the PP-inhibition mechanism, we further found that this inhibitory activity is mediated through the PP-targeting casein kinase 1A1 (CK1α)-β-catenin-NF-κB pathway and CK1α-NRF2-mitochondrial oxidative phosphorylation (OXPHOS) pathway. In addition, a CK1α specific inhibitor D4476 or CK1α siRNA could reverse these inhibitory effects of PP on bacteria-induced inflammatory responses in macrophages. This study reveals a previously unreported mechanism that pyrvinium can inhibit NLRP3 inflammasome and GSDMD-IL-1β inflammatory pyroptosis via targeting suppressing CK1α-β-catenin-NF-κB and CK1α-NRF2-mitochondrial OXPHOS pathways, suggesting that pyrvinium pamoate holds great promise as a host directed therapy (HDT) drug for mycobacterial-induced excessive inflammatory response.

Background/Aims: Exosomal circulating long non-coding RNAs (lncRNAs) in blood are emerging as clinically useful and non-invasive biomarkers for tumor diagnosis. However, normal cells can also secrete exosomes, so it is a prerequisite to obtain tumor-derived exosomes for better understanding of their diagnostic impacts in cancer. In this study, a dual-antibody-functionalized immunoaffinity system was established to isolate exosomes and investigate their lncRNAs expression pattern and clinical significance in prostate cancer (PCa). Methods: A commercially available kit was used to isolate total exosomes, which were then purified by a dual-antibody-functionalized immunoaffinity system. RT-qPCR was performed to detect the expression of exosomal lncRNAs. Receiver operating characteristic (ROC) curves were plotted to assess the diagnostic value. Results: Expression levels of two lncRNAs in tumor-derived exosomes were significantly higher than those in total exosomes. The levels of SAP30L-AS1 were upregulated in benign prostatic hyperplasia (BPH), and SChLAP1 levels were significantly higher in PCa than in BPH and healthy individuals. The area under the ROC curve indicated that SAP30L-AS1 and SChLAP1 had adequate diagnostic value to distinguish PCa from controls. Two lncRNAs separately combined with prostate specific antigen (PSA) possessed a moderate ability for discrimination. SAP30L-AS1 expression level was related to PSA values and tumor invasion. SChLAP1 expression was significantly higher in patients with higher Gleason scores, and was also effective in differentiating between BPH and PCa when the concentration of PSA was in the gray zone. Conclusion: The isolation of tumor-derived exosomes by dual-antibody-functionalized immunoaffinity systems and detection of their lncRNAs in plasma may lead to the identification of suitable biomarkers, with potential diagnostic utility.

The fat mass and obesity-associated protein (FTO), a key RNA N -methyladenosine (m A) demethylase, has been highlighted for its important role in inflammatory response. Emerging evidences link the O-GlcNAcylation to numerous human diseases, particularly inflammation. However, the specific role and underlying mechanism of FTO O-GlcNAcylation in inflammation remain elusive. The FTO O-GlcNAcylation modification was determined by co-immunoprecipitation (Co-IP) assay, metabolic glycan labeling combined with click reaction, and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Chromatin immunoprecipitation (ChIP)-qPCR and dual-luciferase reporter assay were used to determine FOXO1 binding to the 2 promoter and the 2 promoter activity during LPS stimulation. The FTO ubiquitination modification and the interaction between FTO and TRIM21 were detected by confocal microscopy, pull-down, and mass spectrometry analysis. The effects of FTO O-GlcNAcylation on the ubiquitination degradation of FTO were assessed by Co-IP and protein stability assays. The 1 mRNA m A methylation levels were detected by m A-RNA-immunoprecipitation (RIP)-qPCR. The myeloid-specific deletion (mye ) mice, the macrophage depletion and reconstitution experiments, and enzyme-linked immunosorbent assays (ELISA) were used to evaluate inflammatory responses in ( ) or bacterial endotoxin (lipopolysaccharide, LPS) induced sepsis mouse models. We demonstrate that FTO undergoes O-GlcNAcylation specifically at the serine 95 (Ser95) site. LPS enhances FTO O-GlcNAcylation modification levels by increasing the FOXO1-regulated GFAT2 expression. O-GlcNAcylation of FTO promotes TRIM21-mediated K48-ubiquitination degradation of FTO, which further induces suppressor of cytokine signaling ( ) 1 m A methylation, thus sustains SOCS1 protein expression and suppresses multiple inflammatory cytokines IL-1β/IL-6/TNF-α production in LPS-stimulated macrophages. FTO O-GlcNAcylation mutation (S95A) aggravates or LPS-induced sepsis, while FTO O-GlcNAcylation suppresses the hyperinflammatory phenotype in mice. Promotion of O-GlcNAcylation by an OGA inhibitor Thiamet-G alleviates LPS-induced inflammatory responses and septic shock in mice. These findings reveal a mechanism that FTO O-GlcNAcylation promotes its ubiquitination degradation, and thus induces m A methylation and downregulates LPS-mediated inflammatory response, which maintains the negative feedback control of macrophage inflammatory cytokine storm in sepsis. Regulation of FTO O-GlcNAcylation may offer a potential therapeutic strategy for combating endotoxin-induced inflammatory disease and other FTO abnormal expression-associated diseases.

Photodynamic therapy (PDT) has been reported as a possible pathway for the treatment of tumors. The exploration for promising PDT systems thus attracts continuous research efforts. This work focused on an ordered core–shell structure encapsulated by mesoporous SiO2 with the upconverting emission property following a surfactant-assisted sol–gel technique. The mesoporous silica shell possessed a high surface area-to-volume ratio and uniform distribution in pore size, favoring photosensitizer (rose bengal) loading. Simultaneously, upconverting nanocrystals were synthesized and used as the core. After modification via hydrophobic silica, the hydrophobic upconverting nanocrystals became hydrophilic ones. Under near-infrared (NIR) light irradiation, the nanomaterials exhibited strong green upconverting luminescence so that rose bengal could be excited to produce singlet oxygen. The photodynamic therapy (PDT) feature was evaluated using a 1O2 fluorescent indicator. It was found that this core–shell structure generates 1O2 efficiently. The novelty of this core–shell structure was the combination of upconverting nanocrystals with a mesoporous SiO2 shell so that photosensitizer rose bengal could be effectively adsorbed in the SiO2 shell and then excited by the upconverting core.

The prevalence of food allergy (FA) is increasing. Decreases in the diversity of gut microbiota may contribute to the pathogenesis of FA by regulating IgE production of B cells. Intermittent fasting (IF) is a popular diet with the potential to regulate glucose metabolism, boosting immune memory and optimizing gut microbiota. The potential effect of long-term IF on the prevention and treatment of FA is still unknown. Two IF protocols (16 h fasting/8 h feeding and 24 h fasting/24 h feeding) were conducted on mice for 56 days, while the control mice were free to intake food (free diet group, FrD). To construct the FA model, all mice were sensitized and intragastrical challenged with ovalbumin (OVA) during the second half of IF (day 28 to day 56). Rectal temperature reduction and diarrhea were recorded to evaluate the symptoms of FA. Levels of serum IgE, IgG1, Th1/Th2 cytokines, mRNA expression of spleen T cell related transcriptional factors, and cytokines were examined. H&E, immunofluorescence, and toluidine blue staining were used to assess the structural changes of ileum villi. The composition and abundance of gut microbiota were analyzed by 16srRNA sequencing in cecum feces. The diarrhea score and rectal temperature reduction were lower in the two fasting groups compared to the FrD groups. Fasting was associated with lower levels of serum OVA-sIgE, OVA-sIgG1, interleukin (IL)-4 and IL-5, and mRNA expression of IL-4, IL-5, and IL-10 in the spleen. While no significant association was observed in interferon (IFN)-γ, tumor necrosis factor (TNF)-α, IL-6, IL-2 levels. Less mast cell infiltration in ileum was observed in the 16h/8h fasting group compared to the FrD group. ZO-1 expression in the ileum of the two fasting groups was higher in IF mice. The 24h/24h fasting reshaped the gut microbiota, with a higher abundance of and strains compared to the other groups. In an OVA-induced mice FA model, long-term IF may attenuate FA by reducing Th2 inflammation, maintaining the integrity of the intestinal epithelial barrier, and preventing gut dysbiosis.

c-Myc (Myc) is a well-known transcription factor that regulates many essential cellular processes. Myc has been implicated in regulating anti-mycobacterial responses. However, its precise mechanism in modulating mycobacterial immunity remains elusive. Here, we found that a secreted Rv1579c (early secreted target with molecular weight 12 kDa, named EST12) protein, encoded by virulent Mycobacterium tuberculosis ( M.tb ) H37Rv region of deletion (RD)3, induces early expression and late degradation of Myc protein. Interestingly, EST12-induced Myc was further processed by K48 ubiquitin proteasome degradation in E3 ubiquitin ligase FBW7 dependent manner. EST12 protein activates JNK-AP1-Myc signaling pathway, promotes Myc binding to the promoters of IL-6, TNF-α and iNOS, then induces the expression of pro-inflammatory cytokines (IL-6 and TNF-α)/inducible nitric oxide synthase (iNOS)/nitric oxide (NO) to increase mycobacterial clearance in a RACK1 dependent manner, and these effects are impaired by both Myc and JNK inhibitors. Macrophages infected with EST12-deficiency strain (H37RvΔEST12) displayed less production of iNOS, IL-6 and TNF-α. In conclusion, EST12 regulates Myc expression and enhances anti-mycobacterial inflammatory response via RACK1-JNK-AP1-Myc immune pathway. Our finding provides new insights into M.tb -induced immunity through Myc.

Mannose-capped lipoarabinomannan (ManLAM) is a high molecular mass amphipathic lipoglycan identified in pathogenic Mycobacterium tuberculosis (M. tb) and M. bovis Bacillus Calmette-Guérin (BCG). ManLAM, serves as both an immunogen and a modulator of the host immune system, and its critical role in mycobacterial survival during infection has been well-characterized. ManLAM can be recognized by various types of receptors on both innate and adaptive immune cells, including macrophages, dendritic cells (DCs), neutrophils, natural killer T (NKT) cells, T cells and B cells. MamLAM has been shown to affect phagocytosis, cytokine production, antigen presentation, T cell activation and polarization, as well as antibody production. Exploring the mechanisms underlying the roles of ManLAM during mycobacterial infection will aid in improving tuberculosis (TB) prevention, diagnosis and treatment interventions. In this review, we highlight the interaction between ManLAM and receptors, intracellular signalling pathways triggered by ManLAM and its roles in both innate and adaptive immune responses.