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Structural insights into substrate recognition by the type Ⅶ secretion system

Protein & Cell 2020年第2期11卷 124-137页

作者： Shuhui Wang Kaixuan Zhou Xiaolin Yang Bing Zhang Yao Zhao Yu Xiao Xiuna Yang Haitao Yang Luke WGuddat Jun Li Zihe Rao Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Biochemistry and Cell BiologyChinese Academy of SciencesShanghai 200031China State Key Laboratory of Medicinal Chemical Biology College of Life Sciences and College of PharmacyNankai UniversityTianjin 300353China Laboratory of Structural Biology Tsinghua UniversityBeijing 100084China National Laboratory of Biomacromolecules CAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China School of Chemistry and Molecular Biosciences The University of QueenslandBrisbaneQLD 4072Australia University of Chinese Academy of Sciences Beijing 100101China

Type VII secretion systems(T7SSs)are found in many disease related bacteria including Mycobacterium tuberculosis(Mtb).ESX-1[early secreted antigen 6 kilodaltons(ESAT-6)system 1]is one of the five subtypes(ESX-1?5)of T7SSs in Mfb,where it delivers virulence factors into host macrophages during infection.However,little is known about the molecular details as to how this occurs.Here,we provide high-resolution crystal structures of the C-terminal ATPase3 domains of EccC subunits from four different Mtb T7SS subtypes.These structures adopt a classic RecA-like a/p fold with a conserved Mg-ATP binding site.The structure of EccCbl in complex with the C-terminal peptide of EsxB identifies the location of substrate recognition site and shows how the specific signaling module XxxxMxF"for Mtb ESX-1 binds to this site resulting in a translation of the bulge loop.A comparison of all the ATPase3 structures shows there are significant differences in the shape and composition of the signal recognition pockets across the family,suggesting that distinct signaling sequences of substrates are required to be specifically recognized by different T7SSs.A hexameric model of the EccC-ATPase3 is proposed and shows the recognition pocket is located near the central substrate translocation channel.The diameter of the channel is?25-A,with a size that would allow helix-bundle shaped substrate proteins to bind and pass through.Thus,our work provides new molecular insights into substrate recognition for Mtb T7SS subtypes and also a possible transportation mechanism for substrate and/or virulence factor secretion.

关键词： type VII secretion system Mycobacterium tuberculosis ATPase virulence factor substrate recognition

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The zinc transporter Slc39a5 controls glucose sensing and insulin secretion in pancreatic β-cells via Sirt1- and Pgc-1α-mediated regulation of Glut2

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Protein & Cell 2019年第6期10卷 436-449页

作者： Xinhui Wang Hong Gao Wenhui Wu Enjun Xie Yingying Yu Xuyan He Jin Li Wanru Zheng Xudong Wang Xizhi Cao Zhuoxian Meng Ligong Chen Junxia Min Fudi Wang School of Public Health The First Affiliated Hospital Institute of Translational Medicine Zhejiang University School of Medicine Hangzhou 310058 China School of Pharmaceutical Sciences State Key Laboratory of Membrane Biology Tsinghua-Peking Center for Life Sciences School of Life Sciences Tsinghua University Beijing 100084 China Department of Pathology and Pathophysiology Key Laboratory of Disease Proteomics of Zhejiang Province Zhejiang University School of Medicine Hangzhou 310058 China

Zinc levels are high in pancreatic β-cells, and zinc is involved in the synthesis, processing and secretion of insulin in these cells. However, precisely how cellular zinc homeostasis is regulated in pancreatic β-cells is poorly understood. By screening the expression of 14 Slc39a metal importer family member genes, we found that the zinc transporter Slc39a5 is significantly downregulated in pancreatic β-cells in diabetic db/db mice, obese ob/ob mice and high-fat diet-fed mice. Moreover,β-cell-specific Slc39a5 knockout mice have impaired insulin secretion. In addition, Slc39a5-deficient pancreatic islets have reduced glucose tolerance accompanied by reduced expression of Pgc-1α and its downstream target gene Glut2. The down-regulation of Glut2 in Slc39a5-deficient islets was rescued using agonists of Sirt1, Pgc-1α and Ppar-γ. At the mechanistic level, we found that Slc39a5-mediated zinc influx induces Glut2 expression via Sirt1-mediated Pgc-1α activation. These findings suggest that Slc39a5 may serve as a possible therapeutic target for diabetes-related conditions.

关键词： zinc zinc transporter pancreatic islets β-cells insulin secretion

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Autophagy mediates the secretion of macrophage migration inhibitory factor from cardiomyocytes upon serum-starvation

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Science China(Life Sciences) 2019年第8期62卷 1038-1046页

作者： Jimin Wu Xiangning Deng Juan Gao Wei Gao Han Xiao Xinyu Wang Youyi Zhang Department of Cardiology and Institute of Vascular Medicine Peking University Third HospitalNHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory PeptidesKey Laboratory of Molecular Cardiovascular ScienceMinistry of EducationBeijing Key Laboratory of Cardiovascular Receptors Research

Macrophage migration inhibitory factor(MIF) is an inflammatory cytokine. It is elevated early in the blood of acute myocardial infarction patients. However, it is unclear whether and how MIF is released. This study investigated the cellular source and mechanism of MIF release from hearts. An ischemia-mimic treatment induced the secretion of MIF from neonatal rat cardiomyocytes but not from fibroblasts. The treatment did not cause significant leakage of lactate dehydrogenase, suggesting that ischemia induced the MIF secretion without causing severe cell damage. Plasma samples from patients with acute chest pain at the emergency department were collected for the detection of MIF. MIF levels in patients with acute coronary syndrome(ACS)increased early, when cardiac injury markers were not yet elevated, suggesting that ischemia can induce MIF secretion before the occurrence of severe myocardial damage. Serum-starvation caused MIF secretion from rat cardiomyocytes and Langendorffperfused rat hearts. The secretion was suppressed by the inhibition of autophagy by inhibitors or by silencing of Atg5. In conclusion, serum-starvation induces the secretion of MIF from cardiomyocytes via autophagy dependent pathway. Clarifying the mechanism of MIF secretion will be helpful for its application in the early diagnosis and treatment of ACS.

关键词： macrophage migration inhibitory factor cardiomyocyte ischemia autophagy secretion

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Natural killer/T-cell lymphoma with concomitant syndrome of inappropriate antidiuretic hormone secretion: A case report and review of literature

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World Journal of Clinical Cases 2018年第13期6卷 694-702页

作者： Quan-Bo Liu Rui Zheng Department of Respiratory Medicine Shengjing Hospital of China Medical University

We report a case of natural killer(NK)/T-cell lymphoma with concomitant syndrome of inappropriate antidiuretic hormone secretion(SIADH).The patient was a 64-yearold woman with a history of nasopharyngeal carcinoma of over 30 years.She was admitted with a chief complaint of intermittent fever for 2 mo.Palpation after admission indicated a swollen lymph node below the left jaw.Multiple imaging examinations on admission indicated multiple enlarged lymph nodes throughout the body.We performed a left submandibular lymph node biopsy,and the results revealed NK/T-cell lymphoma.A biochemical examination indicated Epstein-Barr virus positivity.At the same time,the patient developed hyponatremia.Based on her laboratory examination and clinical manifestation,decreased plasma osmolality,urine osmolality greater than plasma osmolality,lack of skin swelling,normal blood pressure,normal renal function,no adrenal function detected on serology,and no abnormalities in imaging examination of the adrenal glands,the likelihood of SIADH in the patient was high.After fluid restriction and administration of sodium chloride,the patient’s blood sodium level gradually increased.Subsequently,the immune function of the patient declined,there were severe symptoms of infection,and she died of respiratory failure.NK/T-cell lymphoma associated with SIADH has not,to our knowledge,been previously reported in PubMed.This case emphasizes the importance of monitoring serum ion levels,especially serum sodium,in patients with NK/T-cell lymphoma.

关键词： Epstein-Barr virus Case report Literature review Syndrome of inappropriate antidiuretic hormone secretion Natural killer/T-cell lymphoma

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Muscle secretion of toxic factors,regulated by miR126-5p,facilitates motor neuron degeneration in amyotrophic lateral sclerosis

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Neural Regeneration Research 2019年第6期14卷 969-970页

作者： Roy Maimon Eran Perlson Department of Physiology and Pharmacology Sackler Faculty of MedicineTel Aviv University

Amyotrophic lateral sclerosis(ALS)is a lethal neurodegenerative disease characterized by neuromuscular junction(NMJ)disruption,motor neuron(MN)axon degeneration,and neuronal death.Unfortunately,there is currently no effective treatment available for ALS and consequently,most patients die several years post diagnosis.The neurodegeneration that occurs in ALS is considered to be a non-cell autonomous process involving interactions between the motor neuron and its diverse extracellular microenvironments via an unknown mechanism.Distal Axonopathy is one of the early disease signs;however,the involvement and contribution of neighboring tissues and specifically,the muscle environment to the disease pathology remain controversial.Few works have concluded that muscles play a minor role or none at all in ALS pathology.

关键词： Muscle secretion toxic factors facilitates motor

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New therapeutic perspectives in irritable bowel syndrome: Targeting low-grade inflammation, immuno-neuroendocrine axis, motility, secretion and beyond

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World Journal of Gastroenterology 2017年第36期23卷 6593-6627页

作者： Emanuele Sinagra Gaetano Cristian Morreale Ghazaleh Mohammadian Giorgio Fusco Valentina Guarnotta Giovanni Tomasello Francesco Cappello Francesca Rossi Georgios Amvrosiadis Dario Raimondo Gastroenterology and Endoscopy Unit Fondazione Istituto Giuseppe GiglioContrada Pietra Pollastra Pisciotto Euro-Mediterranean Institute of Science and Technology Department of Experimental Biomedicine and Clinical Neuroscience Section of Human AnatomyUniversity of Palermo Unit of Gastroenterology Ospedali Riuniti Villa Sofia-Vincenzo Cervello Department of Medicine Division of Gastroenterology and HepatologyKarolinska InstitutetKarolinska University Hospital Unit of Internal Medicine Ospedali Riuniti Villa Sofia-Vincenzo Cervello Section of Cardio-Respiratory and Endocrine-Metabolic Diseases Biomedical Department of Internal and Specialist MedicineUniversity of Palermo

Irritable bowel syndrome(IBS)is a chronic,recurring,and remitting functional disorder of the gastrointestinal tract characterized by abdominal pain,distention,and changes in bowel habits.Although there are several drugs for IBS,effective and approved treatments for one or more of the symptoms for various IBS subtypes are needed.Improved understanding of pathophysiological mechanisms such as the role of impaired bile acid metabolism,neurohormonal regulation,immune dysfunction,the epithelial barrier and the secretory properties of the gut has led to advancements in the treatment of IBS.With regards to therapies for restoring intestinal permeability,multiple studies with prebiotics and probiotics are ongoing,even if to date their efficacy has been limited.In parallel,much progress has been made in targeting low-grade inflammation,especially through the introduction of drugs such as mesalazine and rifaximin,even if a better knowledge of the mechanisms underlying the low-grade inflammation in IBS may allow the design of clinical trials that test the efficacy and safety of such drugs.This literature review aims to summarize the findings related to new and investigational therapeutic agents for IBS,most recently developed in preclinical as well as Phase 1 and Phase 2clinical studies.

关键词： Therapy Low grade inflammation Motility secretion Irritable bowel syndrome Immunoendocrine axis

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Dimensionless Study on secretion Clearance of a Pressure Controlled Mechanical Ventilation System with Double Lungs

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Computer Modeling in Engineering & Sciences 2018年第2期114卷 117-139页

作者： Dongkai Shen Qian Zhang Yixuan Wang Huiqing Ge Zujin Luo School of Automation Science and Electrical Engineering Beihang UniversityBeijingPR China The State Key Laboratory of Fluid Power Transmission and Control Zhejiang UniversityHangzhouChina Department of Respiratory Medicine Sir Run Run Shaw HospitalZhejiang University School of MedicineHangzhou 310016ZhejiangChina Department of Respiratory and Critical Care Medicine Beijing Engineering Research Center of Respiratory and Critical Care MedicineBeijing Institute of Respiratory MedicineBeijing Chao-Yang HospitalCapital Medical UniversityBeijing 100043China.

A pressure controlled mechanical ventilator with an automatic secretion clearance function can improve secretion clearance safely and efficiently.Studies on secretion clearance by pressure controlled systems show that these are suited for clinical applications.However,these studies are based on a single lung electric model and neglect the coupling between the two lungs.The research methods applied are too complex for the analysis of a multi-parameter system.In order to understand the functioning of the human respiratory system,this paper develops a dimensionless mathematical model of doublelung mechanical ventilation system with a secretion clearance function.An experiment is designed to verify the mathematical model through comparison of dimensionless experimental data and dimensionless simulation data.Finally,the coupling between the two lungs is studied,and an orthogonal experiment designed to identify the impact of each parameter on the system.

关键词： Dimensionless system mechanical ventilation secretion clearance double lungs pressure control

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The antiangiogenic phloroglucinol hyperforin inhibits the secretion of proMMP-2, proMMP-9 and VEGF-A during apoptosis of primary acute myeloid leukemia cells

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Journal of Cancer Metastasis and Treatment 2021年第1期7卷 588-603页

作者： Faten Merhi Ruoping Tang Ollivier Legrand Florence Nguyen-Khac Santos A.Susin Brigitte Bauvois Centre de Recherche des Cordeliers INSERMSorbonne UniversitéUSPCUniversitéParis DescartesUniversitéParis DiderotParis F-75006France Department of Life&Earth Sciences Faculty of Sciences(I)Lebanese UniversityBeirutLebanon Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Saint-AntoineService d’Hématologie CliniqueParis F-75012France Service Génétique des Tumeurs Département de Biologie et de Pathologie MédicaleGustave Roussy Cancer CamusVillejuif F-94805France Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-SalpêtrièreService d’Hématologie BiologiqueParis F-75013France.

Aim:Angiogenesis is observed in acute myeloid leukemia(AML).AML cells abnormally proliferate and are resistant to death.Positive regulators of angiogenesis,VEGF-A and matrix metalloproteinases(MMPs)2 and 9 are markers of disease status in AML.The natural phloroglucinol hyperforin(HF)displays antitumoral properties of potential pharmacological interest.Herein,we investigated the effects of HF on MMP-2/9 and VEGF-A expression and survival of primary AML cells.Methods:Blood and bone marrow samples were collected in 45 patients with distinct subtypes defined by French American British classification,i.e.,M0,M1,M2,M3,M4,and M5.Levels of MMPs and VEGF-A in leukemic blood cells and culture supernatants were determined by RT-PCR,ELISA,and gelatin zymography(MMPs).The balance between cell death and survival was assessed by flow cytometry with analysis of phosphatidylserine externalization and caspase-3 activation.Results:The administration of HF promoted a caspase-associated apoptosis in primary AML blasts(from blood and bone marrow),but not normal blood cells and monocytes.In addition,HF inhibited the levels of secreted proMMP-2,proMMP-9,and VEGF-A without altering transcripts.The induction of apoptosis by HF significantly paralleled the inhibition of MMP-2/9 and VEGF-A release by HF.No differences were seen in response to the deleterious effects of HF between AML cells of distinct subtypes.Conclusion:Our results suggest that HF,through its proapoptotic and potential antiangiogenic properties(by inhibiting MMP-2/9 and VEGF-A)on primary AML cells,might be a useful experimental agent,in combination with existing drugs,for new therapeutic approaches in the treatment of this incurable disease.

关键词： Acute myeloid leukemia apoptosis hyperforin matrix metalloproteinase VEGF secretion

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Mechanism involved in Danshen-induced fluid secretion in salivary glands

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World Journal of Gastroenterology 2015年第5期21卷 1444-1456页

作者： Fei Wei Mu-Xin Wei Masataka Murakami Division of Physiological Sciences School of Life ScienceGraduate University for Advanced StudiesOkazaki 444-8585Japan Department of Traditional Chinese Medicine The first Affiliated Hospital with Nanjing Medical University Division of Cellular Physiology National Institute for Physiological SciencesNational Institutes of Natural SciencesOkazaki 444-8787Japan

AIM:Danshen's capability to induce salivary fluid secretion and its mechanisms were studied to determine if it could improve xerostomia.METHODS:Submandibular glands were isolated from male Wistar rats under systemic anesthesia with pentobarbital sodium.The artery was cannulated and vascularly perfused at a constant rate.The excretory duct was also cannulated and the secreted saliva was weighed in a cup on an electronic balance.The weight of the accumulated saliva was measured every 3 s and the salivary flow rate was calculated.In addition,the arterio-venous difference in the partial oxygen pressure was measured as an indicator of oxygen consumption.In order to assess the mechanism involved in Dansheninduced fluid secretion,either ouabain(an inhibitor of Na+/K+ ATPase) or bumetanide(an inhibitor of NKCC1) was additionally applied during the Danshen stimulation.In order to examine the involvement of the main membrane receptors,atropine was added to block the M3 muscarinic receptors,or phentolamine was added to block the α1 adrenergic receptors.In order to examine the requirement for extracellular Ca2+,Danshen was applied during the perfusion with nominal Ca2+ free solution.RESULTS:Although Danshen induced salivary fluid secretion,88.7 ± 12.8 μL/g-min,n = 9,(the highest value around 20 min from start of DS perfusion was significantly high vs 32.5 ± 5.3 μL/g-min by carbamylcholine,P = 0.00093 by t-test) in the submandibular glands,the time course of that secretion differed from that induced by carbamylcholine.There was a latency associated with the fluid secretion induced by Danshen,followed by a gradual increasein the secretion to its highest value,which was in turn followed by a slow decline to a near zero level.The application of either ouabain or bumetanide inhibited the fluid secretion by 85% or 93%,and suppressed the oxygen consumption by 49% or 66%,respectively.These results indicated that Danshen activates Na+/K+ ATPase and NKCC1 to maintain Cl- release and K+ release for fluid secretion.Neither atropine or p

关键词： Salivary fluid secretion Xerostomia Chinese herb D

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Changes in expression and secretion patterns of fibroblast growth factor 8 and Sonic Hedgehog signaling pathway molecules during murine neural stem/progenitor cell differentiation in vitro

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Neural Regeneration Research 2012年第22期7卷 1688-1694页

作者： Jiang Lu Kehuan Lu Dongsheng Li State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources Guangxi University Nanning 530004 Guangxi Zhuang Autonomous Region China Department of Anesthesiology Taihe Hospital Hubei University of Medicine Shiyan 442000 Hubei Province China Hubei Key Laboratory of Embryonic Stem Cell Research Taihe Hospital Hubei University of Medicine Shiyan 442000 Hubei Province China

In the present study, we investigated the dynamic expression of fibroblast growth factor 8 and Sonic Hedgehog signaling pathway related factors in the process of in vitro hippocampal neural stem/progenitor cell differentiation from embryonic Sprague-Dawley rats or embryonic Kunming species mice, using fluorescent quantitative reverse transcription-PCR and western blot analyses. Results demonstrated that the dynamic expression of fibroblast growth factor 8 was similar to fibroblast growth factor receptor 1 expression but not to other fibroblast growth factor receptors. Enzyme-linked immunosorbent assay demonstrated that fibroblast growth factor 8 and Sonic Hedgehog signaling pathway protein factors were secreted by neural cells into the intercellular niche. Our experimental findings indicate that fibroblast growth factor 8 and Sonic Hedgehog expression may be related to the differentiation of neural stem/progenitor cells.

关键词： neural stem cells neural progenitor cells fibroblast growth factor 8 Sonic Hedgehog signalpathway secretion dynamic differentiation neurons neural regeneration

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