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Inhibition of KDM6B prevents osteoarthritis by blocking growth plate-like H3K27me3 loss in bivalent genes

Science China Life Sciences 2025年第5期68卷 1423-1436页

作者： Hao Du Yao Zhang Xi Yu Xuanhe You Diwei Wu Ze Du Yongrui Cai Zhenyu Luo Hanpeng Lu Zhixin Liao Bi-Sen Ding Ya Zhao Yan Wang Ke Xiao Fan Yang Fangji Gan Ning Ning Jiancheng Zeng Peiliang Shi Zongke Zhou Shishu Huang Department of Orthopedic Surgery and Orthopedic Research Institute West China HospitalSichuan University Rehabilitation Medicine Center West China HospitalSichuan University Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE State Key Laboratory of BiotherapyWest China Second University HospitalSichuan University Institute of Translational Medicine Medical CollegeYangzhou University Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research College of Animal Science and Technology Sichuan Agricultural University Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province Sichuan Agricultural University Department of Lower Limb Surgery of Sichuan Province Orthopedic Hospital Central Laboratory of Sichuan Province Orthopedic Hospital Brain Cognition and Brain Disease Institute (BCBDI) Shenzhen Institute of Advanced TechnologyChinese Academy of Sciences (CAS)Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions School of Mechanical Engineering Sichuan University Gem Pharmatech (Chengdu) Co. Ltd.

Osteoarthritis(OA) is the most prevalent joint disorder occurring with articular cartilage degradation. It includes a switch from an articular to a growth plate chondrocyte phenotype. Here, we investigated the histone modification profiles and found significant H3K27me3 loss in OA, which led to disease-associated gene expression. Surprisingly, these genes were occupied by both H3K27me3 and H3K4me3 in normal chondrocytes, showing a poised bivalent state. Furthermore, we observed the derepression of similar bivalent genes in growth plate chondrocytes. Finally, a KDM6B inhibitor GSK-J4 prevented the H3K27me3 loss and cartilage damage in the rat OA model. Our results reveal an inherited bivalent epigenetic signature on developmental genes that makes articular chondrocytes prone to hypertrophy and contributes to a promising epigenetic therapy for OA.

关键词： osteoarthritis histone modifications H3K27me3 bivalency growth plate

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Carnitine palmitoyltransferase 1C promotes EMT-associated cisplatin resistance in non-small cell lung cancer cells

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Cancer Biology & Medicine 2025年第1期22卷 48-66页

作者： Renjie Chen Jiahui Wang Shuoyu Huang Xuefeng Hu Xinran He Tiange Zhang Yunhan Hu Huijun Wei Sihui Nian Yushu Huang Zhihao Wu Research Laboratory of Tumor Microenvironment Wannan Medical CollegeWuhu 241001China School of Laboratory Medicine Wannan Medical CollegeWuhu 241001China School of Anesthesiology Wannan Medical CollegeWuhu 241001China School of Medical Imageology Wannan Medical CollegeWuhu 241001China School of Clinical Medicine Wannan Medical CollegeWuhu 241001China Anhui Province Key Laboratory of Active Biological Macro-molecules Research Wannan Medical CollegeWuhu 241001China Provincial Engineering Laboratory for Screening and Re-evaluation of Active Compounds of Herbal Medicines in Southern Anhui Wannan Medical CollegeWuhu 241001China School of Pharmacy Wannan Medical CollegeWuhu 241001China Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation Wannan Medical CollegeWuhu 241001China Anhui Provincial Engineering Research Center for Dental Materials and Application Wannan Medical CollegeWuhu 241001China

Objective:Lung cancer is the most common cause of cancer-related deaths ***-based chemotherapy is one of the main treatment options for patients with non-small cell lung cancer(NSCLC)but the effectiveness of chemotherapy is encumbered by drug ***,understanding the molecular mechanisms underlying chemotherapy resistance is crucial in improving treatment outcomes and ***:The cell viability assay and apoptosis were used to analyze *** blot analysis and wound healing testing were used to evaluate the epithelial-to-mesenchymal transition(EMT).Immunoprecipitation was used for analysis of protein *** activity was determined using the luciferase reporter *** staining was used to determine reactive oxygen species *** expression patterns of EMT markers and carnitine palmitoyltransferase 1C(CPT1C)were determined by Western blot ***:CPT1C,which was shown to be highly expressed in lung cancer,is associated with cisplatin resistance in NSCLC ***1C depletion increased NSCLC cell sensitivity to cisplatin,while overexpression of CPT1C increased NSCLC cell resistance to *** of EMT mediated CPT1C-induced cisplatin *** expression of Snail reversed the increase in cisplatin sensitivity triggered by CPT1C ***,CPT1C was shown to be regulated at the post-translational level and an E3-ubiquitin ligase,NEDD4L,was shown to be a major regulator of CPT1C stability and ***:These data provide evidence for the first time that the lipid metabolism enzyme,CPT1C,mediates resistance to ***,the use of combination therapy with a CPT1C inhibitor may be a promising new avenue in lung cancer treatment.

关键词： CPT1C chemoresistance EMT NEDD4L NSCLC

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Gap-free genome assemblies of two Pyrus bretschneideri cultivars and GWAS analyses identify a CCCH zinc finger protein as a key regulator of stone cell formation in pear fruit

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Plant Communications 2025年第3期6卷 246-262页

作者： Yunpeng Cao Xiaofeng Feng Baopeng Ding Heqiang Huo Muhammad Abdullah Jiayi Hong Lan Jiang Han Wang Risheng Li Yongping Cai Xiaoxu Li Zhichao Xia Rajeev K.Varshney Haifei Hu Mengfei Lin Fei Shen CAS Key Laboratory of Plant Germplasm Enhancement and Specialty Agriculture Wuhan Botanical GardenChinese Academy of SciencesWuhan 430074China College of Life Sciences Anhui Agricultural UniversityHefei 230036China Beijing Life Science Academy Beijing 102209China Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution Yijishan Hospital of Wannan Medical CollegeWuhu 241000China Key Laboratory of Horticultural Crop Germplasm Innovation and Utilization(Co-construction by Ministry and Province) Institute of HorticultureAnhui Academy of Agricultural SciencesHefei 230000China School of Forestry&Landscape Architecture Anhui Agricultural UniversityHefei 230036China Rice Research Institute Guangdong Academy of Agricultural Sciences&Key Laboratory of Genetics and Breeding of High-Quality Rice in Southern China Co-construction by Ministry and Province) Ministry of Agriculture and Rural Affairs&Guangdong Key Laboratory of New Technology in Rice Breeding&Guangdong Rice Engineering LaboratoryGuangzhou 510640China Jiangxi Provincial Key Laboratory of Plantation and High Valued Utilization of Specialty Fruit Tree and Tea Institute of Biological ResourcesJiangxi Academy of SciencesNanchangJiangxiChina Institute of Biotechnology Beijing Academy of Agriculture and Forestry SciencesBeijing 100097China 10Engineering Research Center of Coal-Based Ecological Carbon Sequestration Technology of the Ministry of Education and Key Laboratory of National Forest and Grass Administration for the Application of Graphene in ForestryShanxi Datong UniversityDatong 037009China Department of Environmental Horticulture Mid-Florida Research and Education CenterUniversity of FloridaApopkaFL 32703USA Queensland Alliance for Agriculture and Food Innovation University of Queensland7 BrisbaneBrisbaneQLDAustralia Centre for Crop and Food Innovation WA State Agricultural Biotechnology CentreFood Futures InstituteMurdoch UniversityMurdochWAAustralia

The Chinese white pear(Pyrus bretschneideri)is an economically significant fruit crop *** versions of the *** genome assembly contain numerous gaps and unanchored genetic ***,we generated two high-quality,gap-free genome assemblies for‘Dangshansu’(DS;503.92 Mb)and‘Lianglizaosu’(ZS;509.01 Mb),each anchored to 17 chromosomes,achieving a benchmarking universal single-copy ortholog completeness score of nearly 99.0%.Our genome-wide association studies explored the associations between genetic variations and stone cell traits,revealing a significant association peak on DS chromosome 3 and identifying a novel non-tandem CCCH-type zinc finger gene,designated *** genetic transformation,we verified the pivotal role of PbdsZF in regulation of both lignin biosynthesis and stone cell formation,as it transcriptionally activates multiple genes involved in these *** binding to the CT-rich motifs CT1(CTTTTTTCT)and CT2(CTCTTTTT),PbdsZF significantly influences the transcription of genes essential for lignin production,underscoring its regulatory importance in plant lignin *** study illuminates the complex biology of fruit development and delineates the gene regulatory networks that influence stone cell and lignocellulose formation,thereby enriching genetic resources and laying the groundwork for the molecular breeding of perennial trees.

关键词： Pyrus bretschneideri gap-free genome stone cell formation GWAS transcriptional regulation

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Pluripotent stem cell-derived cardiomyocyte transplantation: marching from bench to bedside

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Science China Life Sciences 2025年

作者： Yi Hong Jiarui Liu Weixuan Wang Hao Li Weijing Kong Xiaoxia Li Wei Zhang Sara Pahlavan Yida Tang Xi Wang Kai Wang Department of Physiology and Pathophysiology School of Basic Medical Sciences State Key Laboratory of Vascular Homeostasis and Remodeling Beijing Advanced Center of Cellular Homeostasis and Aging-Related Diseases Center for Non-coding RNA Medicine Clinical Stem Cell Research Center Peking University Third Hospital Peking University Department of Education Peking University First Hospital Peking University TianXinFu (Beijing) Medical Appliance Co. Ltd. Department of Stem Cells and Developmental Biology Cell Science Research Center Royan Institute for Stem Cell Biology and Technology The Academic Center for Education Culture and Research Department of Cardiology and Institute of Vascular Medicine Key Laboratory of Molecular Cardiovascular Science Ministry of Education Peking University Third Hospital State Key Laboratory of Female Fertility Promotion Department of Obstetrics and Gynecology Peking University Third Hospital Institute of Advanced Clinical Medicine Peking University Hubei Key Laboratory of Embryonic Stem Cell Research Hubei University of Medicine

Cardiovascular diseases such as myocardial infarction, heart failure, and cardiomyopathy, persist as a leading global cause of death. Current treatment options have inherent limitations, particularly in terms of cardiac regeneration due to the limited regenerative capacity of adult human hearts. The transplantation of pluripotent stem cell-derived cardiomyocytes(PSC-CMs) has emerged as a promising and potential solution to address this challenge. This review aims to summarize the latest advancements and prospects of PSC-CM transplantation(PCT), along with the existing constraints, such as immune rejection and engraftment arrhythmias, and corresponding solutions. Encompassing a comprehensive range from fundamental research findings and preclinical experiments to ongoing clinical trials, we hope to offer insights into PCT from bench to bedside.

关键词：

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Ribosomal modification protein rimK-like family member A activates betaine-homocysteine S-methyltransferase 1 to ameliorate hepatic steatosis

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Signal Transduction and Targeted Therapy 2024年第9期9卷 4048-4065页

作者： Han Yan Wenjun Liu Rui Xiang Xin Li Song Hou Luzheng Xu Lin Wang Dong Zhao Xingkai Liu Guoqing Wang Yujing Chi Jichun Yang Department of Physiology and Pathophysiology School of Basic Medical SciencesState Key Laboratory of Vascular Homeostasis and RemodelingCenter for Non-coding RNA MedicinePeking University Health Science CenterBeijing 100191China Department of Endocrinology The Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou 310058China Medical and Health Analysis Center Peking UniversityBeijing 100191China Department of Hepatobiliary Surgery Xi-Jing HospitalFourth Military Medical UniversityXi’an 710032China Department of Endocrinology Beijing Luhe HospitalCapital Medical UniversityBeijing 101100China Department of Hepatobiliary and Pancreatic Surgery General Surgery CentreFirst Hospital of Jilin UniversityChangchun 130061China Key Laboratory of Pathobiology Ministry of Education College of Basic Medical SciencesJilin UniversityChangchun 130012China Department of Central Laboratory and Institute of Clinical Molecular Biology Department of GastroenterologyPeking University People’s HospitalBeijing 100044China Department of Cardiology Peking University Third HospitalBeijing 100191China

nonalcoholic fatty liver disease(NAFLD)is a serious threat to public health,but its underlying mechanism remains poorly *** screening important genes using Gene Importance Calculator(GIC)we developed previously,ribosomal modification protein rimK-like family member A(RIMKLA)was predicted as one essential gene but its functions remained largely *** current study determined the roles of RIMKLA in regulating glucose and lipid *** expression was reduced in livers of human and mouse with *** RIMKLA overexpression ameliorated steatosis and hyperglycemia in obese ***-specific RIMKLA knockout aggravated high-fat diet(HFD)-induced dysregulated glucose/lipid metabolism in ***,RIMKLA is a new protein kinase that phosphorylates betaine-homocysteine S-methyltransferase 1(BHMT1)at threonine 45(Thr45)*** phosphorylation at Thr45 and activation,BHMT1 eliminated homocysteine(Hcy)to inhibit the activity of transcription factor activator protein 1(AP1)and its induction on fatty acid synthase(FASn)and cluster of differentiation 36(CD36)gene transcriptions,concurrently repressing lipid synthesis and uptake in ***45 to alanine(T45A)mutation inactivated BHMT1 to abolish RIMKLA’s repression on Hcy level,AP1 activity,FASn/CD36 expressions,and lipid ***1 overexpression rescued the dysregulated lipid metabolism in RIMKLA-deficient *** summary,RIMKLA is a novel protein kinase that phosphorylates BHMT1 at Thr45 to repress lipid synthesis and *** obese condition,inhibition of RIMKLA impairs BHMT1 activity to promote hepatic lipid deposition.

关键词： metabolism hepatic homocysteine

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Correction: Ribosomal modification protein rimK-like family member A activates betaine-homocysteine S-methyltransferase 1 to ameliorate hepatic steatosis

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Signal Transduction and Targeted Therapy 2025年第1期10卷 471-472页

作者： Han Yan Wenjun Liu Rui Xiang Xin Li Song Hou Luzheng Xu Lin Wang Dong Zhao Xingkai Liu Guoqing Wang Yujing Chi Jichun Yang Department of Physiology and Pathophysiology School of Basic Medical Sciences State Key Laboratory of Vascular Homeostasis and Remodeling Center for Non-coding RNA Medicine Peking University Health Science Center Beijing China Department of Endocrinology The Second Affiliated Hospital School of Medicine Zhejiang University Hangzhou China Department of Cardiology Peking University Third Hospital Beijing China Medical and Health Analysis Center Peking University Beijing China Department of Hepatobiliary Surgery Xi-Jing Hospital Fourth Military Medical University Xi’an China Department of Endocrinology Beijing Luhe Hospital Capital Medical University Beijing China Department of Hepatobiliary and Pancreatic Surgery General Surgery Centre First Hospital of Jilin University Changchun China Key Laboratory of Pathobiology Ministry of Education College of Basic Medical Sciences Jilin University Changchun China Department of Central Laboratory and Institute of Clinical Molecular Biology Department of Gastroenterology Peking University People’s Hospital Beijing China

Correction to:Signal Transduction and Targeted Therapy https://***/10.1038/s41392-024-01914-0,published online 08 August 2024 In the process of collating the raw data,the authors noticed one inadvertent mistake in supplementaryfigure 9f after online publication of the ***β-actin in supplementaryfigure 9d was repeatedly inserted asβ-actin(upper)in supplementaryfigure *** correct data and corresponding original image are provided as *** correction does not affect the keyfindings(the existing published results or the discussion).The original article has been corrected.

关键词： hepatic correction repeatedly

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Liquid-liquid phase separation by SARS-CoV-2 nucleocapsid protein and rna

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细胞研究（英文版） 2020年第12期30卷 1143-1145页

作者： Hui Chen Yang Cui Xuling Han Wei Hu Min Sun Yong Zhang Pei-Hui Wang Guangtao Song Wei Chen Jizhong Lou Shenzhen Baoan Women's and Children's Hospital Jinan UniversityShenzhen Guangdong 518102 China Key Laboratory of RNA Biology CAS Center for Excellence in Biomacromolecules Institute of Biophysics Chinese Academy of Sciences Beijing 100101 China Key Laboratory of RNA Biology CAS Center for Excellence in Biomacromolecules Institute of Biophysics Chinese Academy of Sciences Beijing 100101 China Key Laboratory of RNA Biology CAS Center for Excellence in Biomacromolecules Institute of Biophysics Chinese Academy of Sciences Beijing 100101 China University of Chinese Academy of Sciences Beijing 100084 China Department of Cell Biology and Department of Cardiology of the Second Affiliated Hospital Zhejiang University School of MedicineHangzhou Zhejiang 310058 China Key Laboratory for Biomedical Engineering of Ministry of Education State Key Laboratory for Modern Optical Instrumentation and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases Zhejiang University Han Key Laboratory of RNA Biology CAS Center for Excellence in Biomacromolecules Institute of Biophysics Chinese Academy of Sciences Beijing 100101 China Key Laboratory of RNA Biology CAS Center for Excellence in Biomacromolecules Institute of Biophysics Chinese Academy of Sciences Beijing 100101 China Advanced Medical Research Institute Cheeloo College of Medicine Shandong UniversityJinan Shandong 250012 China Key Laboratory of RNA Biology CAS Center for Excellence in Biomacromolecules Institute of Biophysics Chinese Academy of Sciences Beijing 100101 China Department of Cell Biology and Department of Cardiology of the Second Affiliated Hospital Zhejiang University School of MedicineHangzhou Zhejiang 310058 China Key Laboratory for Biomedical Engineering of Ministry of Education State Key Laboratory for Modern Optical Instrumentation and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases Zhejiang University Han Key Laboratory of RNA Biology CAS C

Dear Editor, The COVID-19 pandemic worldwide is caused by a novel coronavirus SARS-CoV-2(the severe acute respiratory syndrome coronavirus 2).1 After viral invasion into the host cells,the ?30 kb viral genome rna injected is translated into structural and non-structural proteins to replicate viral genome and assemble more viral *** copies of nucleocapsid(N)protein can bind to viral genome rna and pack it into ～100 nm particles,assisting membrane(M)and envelope(E)proteins to efficiently assemble the viral envelope.2 The exact molecular mechanism by which N protein packs up the viral genome still remains elusive.

关键词： Cell biology Molecular biology

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Targeting non-coding rnas to overcome cancer therapy resistance

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Signal Transduction and Targeted Therapy 2022年第5期7卷 1447-1466页

作者： BaoQing Chen Mihnea P.Dragomir Chen Yang Qiaoqiao Li David Horst George A.Calin Department of Radiation Oncology State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer CenterGuangzhouGuangdong 510060China Institute of Pathology Charité-Universitätsmedizin Berlincorporate member of Freie Universität BerlinHumboldt-Universität zu Berlin and Berlin Institute of HealthBerlin 10117Germany Berlin Institute of Health Anna-Louisa-Karsch-Straße 210178 BerlinGermany German Cancer Consortium(DKTK) Partner Site BerlinGerman Cancer Research Center(DKFZ)69210 HeidelbergGermany Department of Translational Molecular Pathology The University of Texas MD Anderson Cancer CenterHoustonTX 77030USA Center for RNA Interference and Non-Coding RNAs The University of Texas MD Anderson Cancer CenterHoustonTX 77030USA

It is now well known that non-coding rnas(ncrnas),rather than protein-coding transcripts,are the preponderant rna ***,particularly micrornas(mirnas),long non-coding rnas(lncrnas),and circular rnas(circrnas),are widely appreciated as pervasive regulators of multiple cancer hallmarks such as proliferation,apoptosis,invasion,metastasis,and genomic *** recent discoveries in cancer therapy,resistance to chemotherapy,radiotherapy,targeted therapy.

关键词： chemotherapy metastasis rnas

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Epitranscriptomic technologies and analyses

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Science China(Life Sciences) 2020年第4期63卷 501-515页

作者： Xiaoyu Li Qiao-Xia Liang Jin-Ran Lin Jinying Peng Jian-Hua Yang Chengqi Yi Yang Yu Qiangfeng Cliff Zhang Ke-Ren Zhou State Key Laboratory of Protein and Plant Gene Research School of Life SciencesPeking UniversityBeijing 100871China MOE Key Laboratory of Gene Function and Regulation State Key Laboratory for BiocontrolSchool of Life SciencesSun Yat-Sen UniversityGuangzhou 510275China The Fifth Affiliated Hospital Sun Yat-Sen UniversityZhuhai 519000China Department of Chemical Biology and Synthetic and Functional Biomolecules Center College of Chemistry and Molecular EngineeringPeking UniversityBeijing 100871China Key Laboratory of RNA Biology CAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing 100101 China MOE Key Laboratory of Bioinformatics Beijing Advanced Innovation Center for Structural BiologyCenter for Synthetic and Systems BiologyTsinghua-Peking Joint Center for Life SciencesSchool of Life SciencesTsinghua UniversityBeijing 100084China

rna can interact with rna-binding proteins(RBPs),mrna,or other non-coding rnas(ncrnas)to form complex regulatory ***-throughput CLIP-seq,degradome-seq,and rna-rna interactome sequencing methods represent powerful approaches to identify biologically relevant ncrna-target and protein-ncrna ***,assigning ncrnas to their regulatory target genes or interacting rna-binding proteins(RBPs)remains technically *** modifications to mrna also play important roles in regulating gene *** of the functional roles of these modifications relies highly on the detection methods *** structure is also critical at nearly every step of the rna life *** this review,we summarize recent advances and limitations in CLIP technologies and discuss the computational challenges of and bioinformatics tools used for decoding the functions and regulatory networks of *** also summarize methods used to detect rna modifications and to probe rna structure.

关键词： ncrna bioinformatics CLIP-seq rna modification quantification and locus-specific detection methods transcriptome-wide sequencing technologies rna structuromes rna structure probing methods

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Mechanical activation of spike fosters SARS-CoV-2 viral infection

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细胞研究（英文版） 2021年第10期31卷 1047-1060页

作者： Wei Hu Yong Zhang Panyu Fei Tongtong Zhang Danmei Yao Yufei Gao Jia Liu Hui Chen Qiao Lu Tenny Mudianto Xinrui Zhang Chuxuan Xiao Yang Ye Qiming Sun ling Zhang Qi Xie Pei-Hui Wang Jun Wang Zhenhai Li Jizhong Lou Wei Chen Department of Cardiology of the Second Affiliated Hospital and Department of Cell Biology Zhejiang University School of MedicineHangzhouZhejiangChina Key Laboratory of RNA Biology CAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijingChina Department of Cardiology of the Second Affiliated Hospital and Department of Cell Biology Zhejiang University School of MedicineHangzhouZhejiangChina School of Mechanical Engineering Zhejiang UniversityHangzhouZhejiangChina Department of Cardiology of the Second Affiliated Hospital and Department of Cell Biology Zhejiang University School of MedicineHangzhouZhejiangChina Department of Hepatobiliary and Pancreatic Surgery The Center for Integrated Oncology and Precision MedicineAffiliated Hangzhou First People's HospitalZhejiang University School of MedicineHangzhouZhejiangChina Department of Pathology New York University Grossman School of MedicineNew YorkNYUSA The Laura and Isaac Perlmutter Cancer Center New York University Langone HealthNew YorkNYUSA Department of Pathology New York University Grossman School of MedicineNew YorkNYUSA Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases the MOE Frontier Science Center for Brain Science & Brain-machine IntegrationState Key Laboratory for Modern Optical Instrumentation Key Laboratory for Biomedical Engineering of the Ministry of EducationCollege of Biomedical Engineering and Instrument ScienceZhejiang UniversityHangzhouZhejiangChina Beijing National Laboratory for Condensed Matter Physics Institute of PhysicsChinese Academy of SciencesBeijingChina Advanced Medical Research Institute Cheeloo College of MedicineShandong UniversityJinanShandongChina Westlake Institute for Advanced Study School of Life SciencesWestlake UniversityHangzhouZhejiangChina Shanghai Key Laboratory of Mechanics in Energy Engineering Shanghai Institute of Applied Mathematics and MechanicsSchool of Mechanics and Engineering ScienceSh

The outbreak of SARS-CoV-2 (SARS2) has caused a global COVID-19 *** spike protein of SARS2 (SARS2-S) recognizes host receptors,including ACE2,to initiate viral entry in a complex biomechanical ***,we reveal that tensile force,generated by bending of the host cell membrane,strengthens spike recognition of ACE2 and accelerates the detachment of spike's S1 subunit from the S2 subunit to rapidly prime the viral fusion ***,such mechano-activation is fulfilled by force-induced opening and rotation of spike's receptor-binding domain to prolong the bond lifetime of spike/ACE2 binding,up to 4 times longer than that of SARS-S binding with ACE2 under 10 pN force application,and subsequently by force-accelerated S1/S2 detachment which is up to ～103 times faster than that in the no-force ***,the SARS2-S D614G mutant,a more infectious variant,shows 3-time stronger force-dependent ACE2 binding and 35-time faster force-induced S1/S2 *** also reveal that an anti-S1/S2 non-RBD-blocking antibody that was derived from convalescent COVlD-19 patients with potent neutralizing capability can reduce S1/S2 detachment by 3 × 106 times under *** study sheds light on the mechano-chemistry of spike activation and on developing a non-RBD-blocking but S1/S2-locking therapeutic strategy to prevent SARS2 invasion.

关键词： Molecular biology Structural biology

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