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TBC1D1 is an energy-responsive polarization regulator of macrophages via governing ROS production in obesity

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Science China Life Sciences 2024年第9期67卷 1899-1914页

作者： Qi Wang Ping Rong Wen Zhang Xinyu Yang Liang Chen Ye Cao Minjun Liu Weikuan Feng Qian Ouyang Qiaoli Chen Hailong Li Hui Liang Fanguo Meng Hong-Yu Wang Shuai Chen State key laboratory of Pharmaceutical Biotechnology Department of Cardiology Nanjing Drum Tower Hospital The Affiliated Hospital of Nanjing University Medical School Model Animal Research CenterSchool of Medicine Nanjing University moe key laboratory of model animal for disease study Department of Endocrinology Nanjing Drum Tower Hospital The Affiliated Hospital of Nanjing University Medical School Model Animal Research Center School of Medicine Nanjing University College of Life Science Anhui Medical University Redox Medical center for Public Health Medical College of Soochow University Department of General Surgery First Affiliated Hospital Nanjing Medical University

Energy status is linked to the production of reactive oxygen species（ROS） in macrophages, which is elevated in obesity. However, it is unclear how ROS production is upregulated in macrophages in response to energy overload for mediating the development of obesity. Here,we show that the Rab-GTPase activating protein（Rab GAP） TBC1D1, a substrate of the energy sensor AMP-activated protein kinase（AMPK）,is a critical regulator of macrophage ROS production and consequent adipose inflammation for obesity development. TBC1D1 deletion decreases, whereas an energy overload-mimetic non-phosphorylatable TBC1D1S231AAmutation increases, ROS production and M1-like polarization in macrophages. Mechanistically, TBC1D1 and its downstream target Rab8a form an energy-responsive complex with NOX2 for ROS generation. Transplantation of TBC1D1S231Abone marrow aggravates diet-induced obesity whereas treatment with an ultra-stable Tt SOD for removal of ROS selectively in macrophages alleviates both TBC1D1S231Amutation-and diet-induced obesity. Our findings therefore have implications for drug discovery to combat obesity.

关键词： TBC1D1 AMPK Rab8a NOX2 ROS inflammation macrophage obesity

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Depletion of Gsdma1/2/3 alleviates PMA-induced epidermal hyperplasia by inhibiting the EGFR–Stat3/Akt pathway

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Journal of Molecular Cell Biology 2024年第1期16卷 29-42页

作者： Qiyao Liu Manyun Li Minli Sun Ruyue Xin Yushu Wang Qin Chen Xiang Gao Zhaoyu Lin moe key laboratory of model animals for disease study State Key Laboratory of Pharmaceutical BiotechnologyJiangsu Key Laboratory of Molecular MedicineModel Animal Research CenterNational Resource Center for Mutant Mice of ChinaNanjing Drum Tower HospitalSchool of MedicineNanjing UniversityNanjing 210061China Department of Oral Surgery Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai 200240China

Homeostasis of the skin barrier is essential for maintaining normal skin *** A(GSDMA)is highly expressed in the skin and associated with many skin diseases,such as melanoma and *** mice,GSDMA is encoded by three gene homologues,namely Gsdma1,Gsdma2,and *** Gsdma3 gain-of-function mutations cause hair loss and skin inflammation,Gsdma3-deficient mice do not show any visible phenotypes in skin and hair *** explore the physiological function of GSDMA,we generated conventional Gsdma1/2/3 knockout(KO)*** mice showed significantly alleviated epidermal hyperplasia and inflammation induced by phorbol 12-myristate 13-acetate(PMA).Furthermore,the alleviation of epidermal hyperplasia depended on the expression of Gsdma1/2/3 specifically in ***,Gsdma1/2/3 depletion downregulated epidermal growth factor receptor(EGFR)ligands,leading to the decreased EGFR–Stat3/Akt *** results demonstrate that depletion of Gsdma1/2/3 alleviates PMA-induced epidermal hyperplasia partially by inhibiting the EGFR–Stat3/Akt pathway.

关键词： GSDMA epidermal hyperplasia PMA Hb-egf EGFR Stat3 Akt

The characterization of protein lactylation in relation to cardiac metabolic reprogramming in neonatal mouse hearts

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Journal of Genetics and Genomics 2024年第7期51卷 735-748页

作者： Tongyu Zhang Yingxi Zhu Xiaochen Wang Danyang Chong Haiquan Wang Dandan Bu Mengfei Zhao Lei Fang Chaojun Li Ministry of Education key laboratory of model animals for disease study Model Animal Research CenterMedical School of Nanjing UniversityNational Resource Center for Mutant MiceNanjingJiangsu 210093China State key laboratory of Reproductive Medicine and Offspring Health China International Joint Research Center on Environment and Human HealthCenter for Global HealthSchool of Public HealthGusu SchoolNanjing Medical UniversityNanjingJiangsu 211166China

In mammals,the neonatal heart can regenerate upon injury within a short time after birth,while adults lose this *** reprogramming has been demonstrated to be critical for cardiomyocyte proliferation in the neonatal ***,we reveal that cardiac metabolic reprogramming could be regulated by altering global protein *** performing 4D label-free proteomics and lysine lactylation(Kla)omics analyses in mouse hearts at postnatal days 1,5,and 7,2297 Kla sites from 980 proteins are identified,among which 1262 Kla sites from 409 proteins are *** clustering analysis reveals that the proteins with altered Kla sites are mainly involved in metabolic *** expression and Kla levels of proteins in glycolysis show a positive correlation while a negative correlation in fatty acid ***,we verify the Kla levels of several differentially modified proteins,including ACAT1,ACADL,ACADVL,PFKM,PKM,and ***,our study reports a comprehensive Kla map in the neonatal mouse heart,which will help to understand the regulatory network of metabolic reprogramming and cardiac regeneration.

关键词： Lactylation Metabolicrep rogramming Postnatal heart regeneration Cell proliferation

Apolipoprotein E4 interferes with lipid metabolism to exacerbate depression-like behaviors in 5xFAD mice

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animal models and Experimental Medicine 2024年第3期7卷 347-361页

作者： Yanju Gong Mingfeng Li Min Liu Xinghan Wu Yanhong Li Chuan Qin Ling Zhang iNHC key laboratory of Human disease Comparative Medicine Beijing Engineering Research Center for Experimental Animal Models of Human Critical DiseasesInternational Center for Technology and lnnovation of Animal ModelComparative Medicine CenterInstitute of Laboratory Animal SciencesChinese Academy of Medical Sciences(CAMS)and Peking Union Medical College(PuMC)BeijingChina Changping National laboratory(CPNL) BeijingChina

Background:Apolipoprotein E4(ApoE4)allele is the strongest genetic risk factor for late-onset Alzheimer's disease,and it can aggravate depressive symptoms in non-AD ***,the impact of ApoE4 on AD-associated depression-l ike behaviors and its underlying pathogenic mechanisms remain ***:This study developed a 5xFAD mouse model overexpressing human ApoE4(E4FAD).Behavioral assessments and synaptic function tests were conducted to explore the effects of ApoE4 on cognition and depression in 5xFAD *** in peripheral and central lipid metabolism,as well as the levels of serotonin(5-HT)andγ-aminobutyric acid(GABA)neurotransmitters in the prefrontal cortex,were *** addition,the protein levels of 24-dehydrocholesterol reductase/glycogen synthase kinase-3 beta/mammalian target of rapamycin(DHCR24/GSK3β/m TOR)and postsynaptic density protein 95/calmodulin-dependent protein kinase II/brain-derived neurotrophic factor(PSD95/CaMK-II/BDNF)were measured to investigate the molecular mechanism underlying the effects of ApoE4 on AD ***:Compared with 5xFAD mice,E4FAD mice exhibited more severe depressionlike behaviors and cognitive *** mice also exhibited increased amyloid-beta deposition in the hippocampus,increased astrocyte numbers,and decreased expression of depression-related neurotransmitters 5-HT and GABA in the prefrontal ***,lipid metabolism disorders were observed in E4FAD,manifesting as elevated low-density lipoprotein cholesterol and reduced high-density lipoprotein cholesterol in peripheral blood,decreased cholesterol level in the prefrontal cortex,and reduced expression of key enzymes and proteins related to cholesterol synthesis and *** expression of proteins related to the DHCR24/GSK3β/m TOR and PSD95/CaMK-II/BDNF pathways was also ***:This study found that ApoE4 overexpression exacerbates depressionlike behaviors in 5xFAD mice and confirmed that ApoE4 reduces co

关键词： 5xFAD mice Alzheimer's disease ApoE4 allele depression like

Overexpression of wild-type HRAS drives non-alcoholic steatohepatitis to hepatocellular carcinoma in mice

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Zoological research 2024年第3期45卷 551-566页

作者： Chen Ling Su-Su Liu Yu-Ya Wang Gui-Tao Huo Yan-Wei Yang Nan Xu Hong Wang Yong Wu Yu-Fa Miao Rui Fu Yu-Wei Zhao Chang-Fa Fan College of Life Sciences Northwest UniversityProvincial Key Laboratory of Biotechnology of Shaanxi ProvinceXi’anShaanxi 710069China Division of animal model research Institute for Laboratory Animal ResourcesNational Institutes for Food and Drug Control(NIFDC)Beijing 102629China National center for Safety Evaluation of Drugs National Institutes for Food and Drug Control(NIFDC)Beijing 100176China Division of HIV/AIDS and Sexually Transmitted Virus Vaccines Institute for Biological Products ControlNational Institutes for Food and Drug Control(NIFDC)Beijing 102629China Division of laboratory animal Monitoring Institute for Laboratory Animal ResourcesNational Institutes for Food and Drug Control(NIFDC)Beijing 102629China

Hepatocellular carcinoma(HCC),a prevalent solid carcinoma of significant concern,is an aggressive and often fatal disease with increasing global incidence rates and poor therapeutic *** etiology and pathological progression of non-alcoholic steatohepatitis(NASH)-related HCC is multifactorial and ***,no single animal model can accurately mimic the full NASH-related HCC pathological progression,posing considerable challenges to transition and mechanistic ***,a novel conditional inducible wild-type human HRAS overexpressed mouse model(HRAS-HCC)was established,demonstrating 100%morbidity and mortality within approximately one month under normal dietary and lifestyle *** symptoms of HCC such as ascites,thrombus,internal hemorrhage,jaundice,and lung metastasis were successfully replicated in ***-depth pathological features of NASH-related HCC were demonstrated by pathological staining,biochemical analyses,and typical marker gene *** murine anti-PD-1 and sorafenib treatment effectively prolonged mouse survival,further confirming the accuracy and reliability of the *** on protein-protein interaction(PPI)network and RNA sequencing analyses,we speculated that overexpression of HRAS may initiate the THBS1-COL4A3 axis to induce NASH with severe fibrosis,with subsequent progression to ***,our study successfully duplicated natural sequential progression in a single murine model over a very short period,providing an accurate and reliable preclinical tool for therapeutic evaluations targeting the NASH to HCC continuum.

关键词： HRAS THBS1 HCC driver factor NASH Fibrosis Cirrhosis HCC Treatment evaluation

LonP1 Links Mitochondria–ER Interaction to Regulate Heart Function

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research 2024年第1期2023卷 595-609页

作者： Yujie Li Dawei Huang Lianqun Jia Fugen Shangguan Shiwei Gong Linhua Lan Zhiyin Song Juan Xu Chaojun Yan Tongke Chen Yin Tan Yongzhang Liu Xingxu Huang Carolyn K.Suzuki Zhongzhou Yang Guanlin Yang Bin Lu The Affiliated Nanhua Hospital and School of Basic Medical Sciences Hengyang Medical SchoolUniversity of South ChinaHengyangHunan 421001China School of laboratory Medicine and Life Sciences Wenzhou Medical UniversityWenzhouZhejiang 325035China National Health Commission key laboratory of Birth Defect research and Prevention Hunan Provincial Maternal and Child Health Care HospitalChangshaHunan 410008China key laboratory of Ministry of Education for TCM Viscera-State Theory and Applications Ministry of Education of ChinaLiaoning University of Traditional Chinese MedicineShenyangLiaoning 110847China key laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic diseases of Zhejiang Province The First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiangChina Hubei key laboratory of Cell Homeostasis College of Life SciencesWuhan UniversityWuhanHubei 430072China Nanjing Maternity and Child Health Care Hospital Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical UniversityNanjing 210004China animal center Wenzhou Medical UniversityWenzhouZhejiang 325035China Department of Cardiology The First Affiliated Hospital of University of South ChinaHengyangHunanChina School of Life Science and Technology Shanghai Tech UniversityShanghai 201210China Department of Microbiology Biochemistry and Molecular GeneticsNew Jersey Medical School-RutgersThe State University of New JerseyNewarkNJUSA State key laboratory of Pharmaceutical Biotechnology Department of CardiologyNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical School and MOE Key Laboratory of Model Animal for Disease StudyModel Animal Research CenterNanjing UniversityNanjing 210061China

Interorganelle contacts and communications are increasingly recognized to play a vital role in cellular function and *** particular,the mitochondria–endoplasmic reticulum(ER)membrane contact site(MAM)is known to regulate ion and lipid transfer,as well as signaling and organelle ***,the regulatory mechanisms of MAM formation and their function are still ***,we identify mitochondrial Lon protease(LonP1),a highly conserved mitochondrial matrix protease,as a new MAM tethering *** removal of LonP1 substantially reduces MAM formation and causes mitochondrial ***,deletion of LonP1 in the cardiomyocytes of mouse heart impairs MAM integrity and mitochondrial fusion and activates the unfolded protein response within the ER(UPR^(ER)).Consequently,cardiac-specific LonP1 deficiency causes aberrant metabolic reprogramming and pathological heart *** findings demonstrate that LonP1 is a novel MAM-localized protein orchestrating MAM integrity,mitochondrial dynamics,and UPR^(ER),offering exciting new insights into the potential therapeutic strategy for heart failure.

关键词： offering programming insight

Semisynthesis of homogeneous spike RBD glycoforms from SARS-CoV-2 for profiling the correlations between glycan composition and function

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National Science Review 2024年第2期11卷 145-154页

作者： Farong Ye Cheng Li Feng-Liang Liu Xinliang Liu Peng Xu Rong-Hua Luo Wenping Song Yong-Tang Zheng Tianlei Ying Biao Yu Ping Wang center for Chemical Glycobiology Frontiers Science Center for Transformative Molecules Zhangjiang Institute for Advanced Study School of Chemistry and Chemical Engineering Shanghai Jiao Tong University moe/NHC/CAMS key laboratory of Medical Molecular Virology Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection Shanghai Institute of Infectious Disease and BiosecurityShanghai Engineering Research Center for Synthetic ImmunologySchool of Basic Medical Sciences Shanghai Medical College Fudan University key laboratory of animal models and Human disease Mechanisms of Chinese Academy of Sciences/key laboratory of Bioactive Peptides of Yunnan Province Center for Biosafety Mega-Science Kunming Institute of ZoologyChinese Academy of Sciences State key laboratory of Bioorganic and Natural Products Chemistry Center for Excellence in Molecular Synthesis Shanghai Institute of Organic Chemistry Chinese Academy of Sciences Shenzhen research Institute of Shanghai Jiao Tong University

Vaccines have been the primary remedy in the global fight against coronavirus disease 2019（COVID-19）.The receptor-binding domain（RBD） of the spike protein, a critical viral immunogen, is affected by the heterogeneity of its glycan structures and relatively low immunogenicity. Here, we describe a scalable synthetic platform that enables the precise synthesis of homogeneously glycosylated RBD, facilitating the elucidation of carbohydrate structure–function relationships. Five homogeneously glycosylated RBDs bearing biantennary glycans were prepared, three of which were conjugated to T-helper epitope(Tpep) from tetanus toxoid to improve their weak immune response. Relative to natural HEK293-derived RBD, synthetic RBDs with biantennary N-glycan elicited a higher level of neutralising antibodies against SARS-CoV-2 in mice. Furthermore, RBDs containing Tpepelicited significant immune responses in transgenic mice expressing human angiotensin-converting enzyme 2. Our collective data suggest that trimming the N-glycans and Tpepconjugation of RBD could potentially serve as an effective strategy for developing subunit vaccines providing efficient protection.

关键词： peptide ligation glycosylation glycoprotein

The virulence regulator AbsR in avian pathogenic Escherichia coli has pleiotropic effects on bacterial physiology

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Journal of Integrative Agriculture 2024年第2期23卷 649-668页

作者： Dongfang Zhao Haobo Zhang Xinyang Zhang Fengwei Jiang Yijing Li Wentong Cai Ganwu Li State key laboratory for animal disease Control and Prevention Harbin Veterinary Research InstituteChinese Academy of Agricultural SciencesHarbin 150069China College of Veterinary Medicine Northeast Agricultural UniversityHarbin 150038China National animal Tuberculosis Reference laboratory Division of Zoonoses SurveillanceChina Animal Health and Epidemiology CenterQingdao 266032China Department of Veterinary Diagnostic and Production animal Medicine College of Veterinary MedicineIowa State UniversityAmesIowa 50011-1134the United States

Avian pathogenic Escherichia coli(APEC)belonging to extraintestinal pathogenic ***(ExPEC)can cause severe infections in extraintestinal tissues in birds and humans,such as the lungs and ***(microcin production regulation,locus A,herein renamed AbsR,a blood survival regulator),a member of the MarR(multiple antibiotic resistance regulator)transcriptional regulator family,governs the expression of capsule biosynthetic genes in human ExPEC and represents a promising druggable target for ***,a deep understanding of the AbsR regulatory mechanism as well as its regulon is *** this study,we present a systems-level analysis of the APEC AbsR regulon using ChIP-Seq(chromatin immunoprecipitation sequencing)and RNA-Seq(RNA sequencing)*** found that AbsR directly regulates 99 genes and indirectly regulates 667 ***,we showed that:1)AbsR contributes to antiphagocytotic effects by macrophages and virulence in a mouse model for systemic infection by directly activating the capsular gene cluster;2)AbsR positively impacts biofilm formation via direct regulation of the T2SS(type II secretion system)but plays a marginal role in virulence;and 3)AbsR directly upregulates the acid tolerance signaling system EvgAS to withstand acid stress but is dispensable in ExPEC ***,our data indicate that the role of AbsR in virulence gene regulation is relatively conserved in ExPEC ***,this study provides a comprehensive analysis of the AbsR regulon and regulatory mechanism,and our data suggest that AbsR likely influences virulence primarily through the control of capsule ***,we found that AbsR severely represses the expression of the type I-F CRISPR(clustered regularly interspaced short palindromic repeats)-Cas(CRISPR associated)systems,which could have implications in CRISPR biology and application.

关键词： avian pathogenic Escherichia coli(APEC) extraintestinal pathogenic Escherichia coli(ExPEC) AbsR RNA-Seq ChIP-Seq gene regulation

The ubiquitin codes in cellular stress responses

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Protein & Cell 2024年第3期15卷 157-190页

作者： Xiangpeng Sheng Zhixiong Xia Hanting Yang Ronggui Hu key laboratory of Systems Health Science of Zhejiang Province School of Life ScienceHangzhou Institute for Advanced StudyUniversity of Chinese Academy of SciencesHangzhou 310024China State key laboratory of Molecular Biology Shanghai Institute of Biochemistry and Cell BiologyCenter for Excellence in Molecular Cell ScienceChinese Academy of SciencesShanghai 200031China State key laboratory of animal disease Control Harbin Veterinary Research InstituteChinese Academy of Agricultural SciencesHarbin 150069China Department of Neurology State Key Laboratory of Medical NeurobiologyInstitute for Translational Brain ResearchMOE Frontiers Center for Brain ScienceZhongshan HospitalFudan UniversityShanghai 200032China

Ubiquitination/ubiquitylation,one of the most fundamental post-translational modifications,regulates almost every critical cellular process in *** evidence has shown that essential components of numerous biological processes undergo ubiquitination in mammalian cells upon exposure to diverse stresses,from exogenous factors to cellular reactions,causing a dazzling variety of functional *** forms of ubiquitin sig-nals generated by ubiquitylation events in specific milieus,known as ubiquitin codes,constitute an intrinsic part of myriad cellular stress *** ubiquitination events,leading to proteolytic turnover of the substrates or just switch in functionality,initiate,regulate,or supervise multiple cellular stress-associated responses,supporting adaptation,homeostasis recovery,and survival of the stressed *** this review,we attempted to summarize the crucial roles of ubiquitination in response to different environmental and intracellular stresses,while discussing how stresses modulate the ubiquitin *** review also updates the most recent advances in understanding ubiquitination machinery as well as different stress responses and discusses some important questions that may warrant future investigation.

关键词： ubiquitin E3 ligase environmental stresses intercellular stresses stress response homeostasis