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ZCCHC3 modulates TLR3-mediated signaling by promoting recruitment of TRIF to TLR3

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Journal of Molecular Cell Biology 2020年第4期12卷 251-262页

作者： Ru Zang Huan Lian Xuan Zhong Qing Yang Hong-Bing Shu Department of Infectious Diseases Frontier Science Center for Immunology and MetabolismMedical Research InstituteZhongnan Hospital of Wuhan UniversityWuhan UniversityWuhan 430071China

Toll-like receptor 3(TLR3)-mediated signaling is important for host defense against RNA virus.Upon viral RNA stimulation,toll and interleukin-1 receptor domain-containing adaptor inducing IFN-p(TRIF)is recruited to TLR3 and then undergoes oligomerization,which is required for the recruitment of downstream molecules to transmit signals.Here,we identified zinc finger CCHC-type containing 3(ZCCHC3)as a positive regulator of TLR3-mediated signaling.Overexpression of ZCCHC3 promoted transcription of downstream antiviral genes stimulated by the synthetic TLR3 ligand poly(I:C).ZCCHC3-deficiency markedly inhibited TLR3-but not TLR4-mediated induction of type I interferons(IFNs)and proinflammatory cytokines.Zcc/7c3-/-mice were more resistant to poly(l:C)-but not lipopolysaccharide-induced inflammatory death.Mechanistically,ZCCHC3 promoted recruitment of TRIF to TLR3 after poly(l:C)stimulation.Our findings reveal that ZCCHC3 plays an important role in TLR3-mediated innate immune response by promoting the recruitment of TRIF to TLR3 after ligand stimulation.

关键词： TLR3 TRIF ZCCHC3 innate immune response signaling

The crucial role of PTS1 in the adaptive evolution of AGT subcellular localization among herbivorous mammals

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The crucial role of PTS1 in the adaptive evolution of AGT su...

Stepwise differentiation of functional pancreatic β cells from human pluripotent stem cells

第十六届全国野生动物生态与资源保护学术研讨会

作者： Chen Huang Bingjun Wang Jianglong Yu Huabin Zhao Department of Ecology College of Life Sciences Frontier Science Center for Immunology and Metabolism Wuhan University

The herbivorous diet in mammals is one of the diverse diets that emerged from their insectivorous mammal ancestors during evolution, promoting the emergence of new adaptive nutritional strategies in mammals. In order to investigate the adaptive evolution driven by diet in herbivorous mammals, we conducted a study on the subcellular localization of alanine: glyoxylate aminotransferase(AGT), which has the ability to target both mitochondria and peroxisome. We specifically examined the ability of N-terminal mitochondrial targeting sequence(MTS) and C-terminal peroxisomal targeting sequence(PTS1) that mediate the localization of AGT to these organelles. Through cell-based immunofluorescence assays, we observed higher efficiencies of AGT peroxisomal targeting in herbivores. We also found that peroxisomal targeting efficiencies of AGT without PTS1 exhibit varying degrees of decreases in different mammals. Additionally, our findings revealed the presence of numerous nonfunctional MTS and highly conserved PTS1 in herbivores and PTS1 is under strong purifying selection in 37 examined species. We observed a significant positive correlation between peroxisomal targeting efficiencies of AGT and proportions of plant tissue in mammalian diets, confirming the influence of dietary composition on AGT subcellular localization. Furthermore, our experimental results led us to explore the mechanisms underlying AGT subcellular localization, revealing that PTS1 has an ability to influence AGT localization regardless of the presence or absence of functional MTS, particularly in herbivores. This study highlighted the significant influence of PTS1 on the subcellular localization of AGT and contributes to our understanding of adaptive evolution in herbivorous mammals.

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Cell Regeneration 2022年第1期11卷 227-245页

作者： Wenwen Jin Wei Jiang Department of Biological Repositories Frontier Science Center for Immunology and MetabolismMedical Research InstituteZhongnan Hospital of Wuhan UniversityWuhan 430071China Human Genetics Resource Preservation center of Wuhan University Wuhan 430071China

Pancreaticβcells differentiated from stem cells provide promise for cell replacement therapy of diabetes.Human pluripotent stem cells could be differentiated into definitive endoderm,followed by pancreatic progenitors,and then subjected to endocrinal differentiation and maturation in a stepwise fashion.Many achievements have been made in making pancreaticβcells from human pluripotent stem cells in last two decades,and a couple of phase I/II clinical trials have just been initiated.Here,we overview the major progresses in differentiating pancreaticβcells from human pluripotent stem cells with the focus on recent technical advances in each differentiation stage,and briefly discuss the current limitations as well.

关键词： Pancreaticβcell Human pluripotent stem cells Stepwise differentiation Diabetes mellitus

Dephosphorylation of cGAS by PPP6C impairs its substrate binding activity and innate antiviral response

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Protein & Cell 2020年第8期11卷 584-599页

作者： Mi Li Hong-Bing Shu Department of Infectious Diseases Frontier Science Center for Immunology and MetabolismMedical Research InstituteZhongnan Hospital of Wuhan UniversityCollege of Life SciencesWuhan UniversityWuhan 430071China

The cyclic GMP-AMP (cGAMP) synthase (cGAS) plays a critical role in host defense by sensing cytosollc DNA derived from microbial pathogens or mls-located cellular DNA.Upon DNA binding,cGAS utilizes GTP and ATP as substrates to synthesize cGAMP,leading to MITA-mediated innate immune response.In this study,we identified the phosphatase PPP6C as a negative regulator of cGASmediated innate immune response.PPP6C is constitutively associated with cGAS in un-stimulated cells.DNA virus infection causes rapid disassociation of PPP6C from cGAS,resulting in phosphorylation of human cGAS S435 or mouse cGAS S420 in its catalytic pocket.Mutation of this eerine residue of cGAS impairs its ability to synthesize cGAMP upon DNA virus infection.In vitro experiments indicate that S420-phosphorylated mcGAS has higher affinity to GTP and enzymatic activity.PPP6Cdeficiency promotes innate immune response to DNA virus in various cells.Our findings suggest that PPP6Cmediated dephosphorylation of a catalytic pocket serine residue of cGAS impairs its substrate binding activity and innate immune response,which provides a mechanism for keeping the DNA sensor cGAS inactive in the absence of infection to avoid autoimmune response.

关键词： DNA virus PPP6C cGAS innate immune response phosphorylation substrate binding

C1QTNF5 is a novel attachment factor that facilitates the entry of influenza A virus

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Virologica Sinica 2024年第2期39卷 277-289页

作者： Lei Yu Xinjin Liu Xiaoqin Wei Junrui Ren Xueyun Wang Shuwen Wu Ke Lan State Key Laboratory of Virology Medical Research InstituteCollege of Life SciencesWuhan UniversityWuhan430072China Frontier Science Center for Immunology and Metabolism Wuhan UniversityWuhan430072China Taikang center for Life and Medical sciences Wuhan UniversityWuhan430072China

Influenza A virus(IAV)binds sialic acid receptors on the cell surface to enter the host cells,which is the key step in initiating infection,transmission and pathogenesis.Understanding the factors that contribute to the highly efficient entry of IAV into human cells will help elucidate the mechanism of viral entry and pathogenicity,and provide new targets for intervention.In the present study,we reported a novel membrane protein,C1QTNF5,which binds to the hemagglutinin protein of IAV and promotes IAV infection in vitro and in vivo.We found that the HA1 region of IAV hemagglutinin is critical for the interaction with C1QTNF5 protein,and C1QTNF5 interacts with hemagglutinin mainly through its N-terminus(1–103 aa).In addition,we further demonstrated that overexpression of C1QTNF5 promotes IAV entry,while blocking the interaction between C1QTNF5 and IAV hemagglutinin greatly inhibits viral entry.However,C1QTNF5 does not function as a receptor to mediate IAV infection in sialic acid-deficient CHO-Lec2 cells,but promotes IAV to attach to these cells,suggesting that C1QTNF5 is an important attachment factor for IAV.This work reveals C1QTNF5 as a novel IAV attachment factor and provides a new perspective for antiviral strategies.

关键词： C1QTNF5 Influenza A virus Viral entry Hemagglutinin Attachment factor

MYC in T-cell acute lymphoblastic leukemia: functional implications and targeted strategies

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Blood science 2021年第3期3卷 65-70页

作者： Qilong Li Sa Pan Ting Xie Hudan Liu Department of Hematology Zhongnan Hospital of Wuhan UniversityWuhan 430071China Frontier Science Center for Immunology and Metabolism Medical Research InstituteWuhan UniversityWuhan 430071China

T-cell acute lymphoblastic leukemia(T-ALL)is an aggressive hematological cancer that frequently occurs in children and adolescents,which results from the transformation of immature T-cell progenitors.Aberrant cell growth and proliferation of T-ALL lymphoblasts are sustained by activation of strong oncogenic drivers.Mounting evidence highlights the critical role of the NOTCH1-MYC highway toward the initiation and progression of T-ALL.MYC has been emphasized as a primary NOTCH1 transcriptional target impinging in leukemia-initiating cell activity particularly responsible for disease onset and relapse.These findings lay a foundation of T-ALL as an ideal disease model for studying MYC-mediated cancer.The biology of MYC deregulation in T-ALL supports innovative strategies for therapeutic targeting of MYC.To summarize the relevant literature and data in recent years,we here provide a comprehensive overview of the functional importance of MYC in T-ALL development,and the molecular mechanisms underlying MYC deregulation in T-ALL.Finally,we illustrate the innovative MYC-targeted approaches that have been evaluated in pre-clinical models and shown significant efficacy.Given the complexity of T-ALL molecular pathogenesis,we propose that a combination of anti-MYC strategies with conventional chemotherapies or other targeted/immunotherapies may provide the most durable response,especially for those patients with relapsed and refractory T-ALL.

关键词： MYC T-ALL Targeted therapy

Regulation of cancer cell metabolism:oncogenic MYC in the driver’s seat

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Signal Transduction and Targeted Therapy 2020年第1期5卷 1419-1429页

作者： Yang Dong Rongfu Tu Hudan Liu Guoliang Qing Department of Urology Zhongnan Hospital of Wuhan UniversityWuhan 430071China frontier science center for immunology&metabolism Medical Research InstituteWuhan UniversityWuhan 430071China

Cancer cells must rewire cellular metabolism to satisfy the demands of unbridled growth and proliferation.As such,most human cancers differ from normal counterpart tissues by a plethora of energetic and metabolic reprogramming.Transcription factors of the MYC family are deregulated in up to 70%of all human cancers through a variety of mechanisms.Oncogenic levels of MYC regulates almost every aspect of cellular metabolism,a recently revisited hallmark of cancer development.Meanwhile,unrestrained growth in response to oncogenic MYC expression creates dependency on MYC-driven metabolic pathways,which in principle provides novel targets for development of effective cancer therapeutics.In the current review,we summarize the significant progress made toward understanding how MYC deregulation fuels metabolic rewiring in malignant transformation.

关键词： metabolism cancer Cancer

Di-and tri-methylation of histone H3K36 play distinct roles in DNA double-strand break repair

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science China Life sciences 2024年第6期67卷 1089-1105页

作者： Runfa Chen Meng-Jie Zhao Yu-Min Li Ao-Hui Liu Ru-Xin Wang Yu-Chao Mei Xuefeng Chen Hai-Ning Du Hubei Key Laboratory of Cell Homeostasis College of Life Sciences Tai Kang Center for Life and Medical Sciences Frontier Science Center for Immunology and Metabolism Hubei Clinical Research Center of Emergency and Resuscitation Emergency Center of Zhongnan Hospital Wuhan University Hubei Key Laboratory of Cell Homeostasis College of Life Sciences Tai Kang Center for Life and Medical Sciences Frontier Science Center for Immunology and Metabolism Wuhan University

Histone H3 Lys36(H3K36) methylation and its associated modifiers are crucial for DNA double-strand break(DSB) repair, but the mechanism governing whether and how different H3K36 methylation forms impact repair pathways is unclear. Here, we unveil the distinct roles of H3K36 dimethylation(H3K36me2) and H3K36 trimethylation(H3K36me3) in DSB repair via non-homologous end joining(NHEJ) or homologous recombination(HR). Yeast cells lacking H3K36me2 or H3K36me3 exhibit reduced NHEJ or HR efficiency. y Ku70 and Rfa1 bind H3K36me2-or H3K36me3-modified peptides and chromatin, respectively. Disrupting these interactions impairs y Ku70 and Rfa1 recruitment to damaged H3K36me2-or H3K36me3-rich loci, increasing DNA damage sensitivity and decreasing repair efficiency. Conversely,H3K36me2-enriched intergenic regions and H3K36me3-enriched gene bodies independently recruit y Ku70 or Rfa1 under DSB stress.Importantly, human KU70 and RPA1, the homologs of y Ku70 and Rfa1, exclusively associate with H3K36me2 and H3K36me3 in a conserved manner. These findings provide valuable insights into how H3K36me2 and H3K36me3 regulate distinct DSB repair pathways,highlighting H3K36 methylation as a critical element in the choice of DSB repair pathway.

关键词： histone H3K36 methylation Ku70 RPA non-homologous end joining homologous recombination

The membrane-associated ubiquitin ligases MARCH2 and MARCH3 target IL-5 receptor alpha to negatively regulate eosinophilic airway inflammation

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Cellular & Molecular immunology 2022年第10期19卷 1117-1129页

作者： Lin-Wen Zeng Lu Feng Rui Liu Heng Lin Hong-Bing Shu Shu Li Department of Infectious Diseases Zhongnan Hospital of Wuhan UniversityMedical Research InstituteFrontier Science Center for Immunology and MetabolismResearch Unit of Innate Immune and Inflammatory Diseases(2019RU063)Chinese Academy of Medical SciencesWuhan UniversityWuhan430071China

Interleukin 5(IL-5)plays crucial roles in type 2-high asthma by mediating eosinophil maturation,activation,chemotaxis and survival.Inhibition of IL-5 signaling is considered a strategy for asthma treatment.Here,we identified MARCH2 and MARCH3 as critical negative regulators of IL-5-triggered signaling.MARCH2 and MARCH3 associate with the IL-5 receptorαchain(IL-5Rα)and mediate its K27-linked polyubiquitination at K379 and K383,respectively,and its subsequent lysosomal degradation.Deficiency of MARCH2 or MARCH3 modestly increases the level of IL-5Rαand enhances IL-5-induced signaling,whereas double knockout of MARCH2/3 has a more dramatic effect.March2/3 double knockout markedly increases the proportions of eosinophils in the bone marrow and peripheral blood in mice.Double knockout of March2/3 aggravates ovalbumin(OVA)-induced eosinophilia and causes increased inflammatory cell infiltration,peribronchial mucus secretion and production of Th2 cytokines.Neutralization of Il-5 attenuates OVA-induced airway inflammation and the enhanced effects of March2/3 double deficiency.These findings suggest that MARCH2 and MARCH3 play redundant roles in targeting IL-5Rαfor degradation and negatively regulating allergic airway inflammation.

关键词： MARCH2/3 IL-5Rα Polyubiquitination Eosinophil Airway inflammation