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Optimizing ABA-based chemically induced proximity for enhanced intracellular transcriptional activation and modification response to ABA

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Science China Life Sciences 2024年

作者： Zeng Zhou Yue-Qi Wang Xu-Nan Zheng Xiao-Hong Zhang Lu-Yao Ji Jun-You Han Ze-Cheng Zuo Wei-Liang Mo Li Zhang College of Life Sciences Fujian Agriculture and Forestry University Basic Forestry and proteomics Research Center Fujian Agriculture and Forestry University Jilin Province Engineering laboratory of Plant Genetic Improvement College of Plant Science Jilin University

Abscisic acid(ABA)-based chemically induced proximity(CIP) is primarily mediated by the interaction of the ABA receptor pyrabactin resistance 1-like 1(PYL1) and the 2C-type protein phosphatase ABI1, which confers ABA-induced proximity to their fusion proteins, and offers precise temporal control of a wide array of biological processes. However, broad application of ABA-based CIP has been limited by ABA response intensity. In this study, we demonstrated that ABA-induced interaction between another ABA receptor pyrabactin resistance 1(PYR1) and ABI1 exhibited higher ABA response intensity than that between PYL1 and ABI1 in HEK293T cells. We engineered PYR1-ABI1and PYL1-ABI1 into ABA-induced transcriptional activation tools in mammalian cells by integration with CRISPR/dCas9 and found that the tool based on PYR1-ABI1 demonstrated better ABA response intensity than that based on PYL1-ABI1 for both exogenous and endogenous genes in mammalian cells. We further achieved ABA-induced RNA m6A modification installation and erasure by combining ABA-induced PYR1-ABI1 interaction with CRISPR/dCas13, successfully inhibiting tumor cell proliferation. We subsequently improved the interaction of PYR1-ABI1 through phage-assisted continuous evolution(PACE), successfully generating a PYR1 mutant(PYR1m) whose interaction with ABI1 exhibited a higher ABA response intensity than that of the wild-type. In addition, we tested the transcriptional activation tool based on PYRm-ABI1 and found that it also showed a higher ABA response intensity than that of the wild type. These results demonstrate that we have developed a novel ABA-based CIP and further improved upon it using PACE, providing a new approach for the modification of other CIP systems.

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Multiomics analysis reveals metabolic subtypes and identifies diacylglycerol kinase α (DGKA) as a potential therapeutic target for intrahepatic cholangiocarcinoma

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Cancer Communications 2024年第2期44卷 226-250页

作者： Weiren Liu Huqiang Wang Qianfu Zhao Chenyang Tao Weifeng Qu Yushan Hou Run Huang Zimei Sun Guiqi Zhu Xifei Jiang Yuan Fang Jun Gao Xiaoling Wu Zhixiang Yang Rongyu Ping Jiafeng Chen Rui Yang Tianhao Chu Jian Zhou Jia Fan Zheng Tang Dong Yang Yinghong Shi Department of Liver Surgery and Transplantation Liver Cancer InstituteZhongshan HospitalFudan UniversityKey Laboratory of Carcinogenesis and Cancer Invasion of Ministry of EducationShanghaiP.R.China Research Unit of Liver cancer Recurrence and Metastasis Chinese Academy of Medical SciencesBeijingP.R.China State Key laboratory of Medical proteomics Beijing Proteome Research CenterNational Center for Protein Sciences(Beijing)Beijing Institute of LifeomicsBeijingP.R.China

Background:Intrahepatic cholangiocarcinoma(iCCA)is a highly heteroge-neous and lethal hepatobiliary tumor with few therapeutic *** metabolic reprogramming of tumor cells plays an essential role in the develop-ment of tumors,while the metabolic molecular classification of iCCA is largely ***,we performed an integrated multiomics analysis and metabolic classification to depict differences in metabolic characteristics of iCCA patients,hoping to provide a novel perspective to understand and treat ***:We performed integrated multiomics analysis in 116 iCCA samples,including whole-exome sequencing,bulk RNA-sequencing and proteome *** on the non-negative matrix factorization method and the protein abundance of metabolic genes in human genome-scale metabolic models,the metabolic subtype of iCCA was *** and prognostic gene analy-ses were used to compare overall survival(OS)differences between metabolic *** proliferation analysis,5-ethynyl-2’-deoxyuridine(EdU)assay,colony formation assay,RNA-sequencing and Western blotting were performed to investigate the molecular mechanisms of diacylglycerol kinaseα(DGKA)in iCCA ***:Three metabolic subtypes(S1-S3)with subtype-specific biomarkers of iCCA were *** metabolic subtypes presented with distinct prog-noses,metabolic features,immune microenvironments,and genetic *** S2 subtype with the worst survival showed the activation of some special metabolic processes,immune-suppressed microenvironment and Kirsten ratsar-coma viral oncogene homolog(KRAS)/AT-rich interactive domain 1A(ARID1A)*** the S2 subtype-specific upregulated proteins,DGKA was further identified as a potential drug target for iCCA,which promoted cell proliferation by enhancing phosphatidic acid(PA)metabolism and activating mitogen-activated protein kinase(MAPK)***:Viamultiomics analyses,we identified three metabolic subtypes of iCCA,revealing

关键词： diacylglycerol kinaseα intrahepatic cholangiocarcinoma MAPK signaling metabolic classifi-cation multiomics analysis phosphatidic acid metabolism

Data-driven drug repositioning using olfactory omics profiles:challenges and perspectives in neurodegeneration

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Neural Regeneration Research 2025年第7期20卷 1997-1998页

作者： Paz Cartas-Cejudo Adriana Cortés Mercedes Lachén-Montes Elena Anaya-Cubero Joaquín Fernández-Irigoyen Enrique Santamaría Clinical Neuroproteomics Unit Proteomics PlatformNavarrabiomedHospitalario Universitario de Navarra(HUN)Universidad Pública de Navarra(UPNA)IdiSNANavarra Institute for Health ResearchPamplonaSpain

Data-driven drug repositioning using olfactory omics profiles-challenges and perspectives in neurodegeneration:Neurodegenerative diseases are characterized by progressive degeneration and loss of neuronal function in the central nervous *** diseases are often characterized as proteinopathies,which are disorders primarily driven by the aggregation or misfolding of specific amyloid proteins within cells,leading to their dysfunction and eventual *** the gain-of-function hypothesis related to the aggregation of these proteins,recently,an alternative hypothesis regarding the loss-of-function of the soluble monomeric proteins during the process of aggregation into amyloids is gaining *** last event is called proteinopenia and refers to conditions characterized by a deficiency or decrease in the levels of specific soluble proteins in the body(Ezzat et al.,2023).It has been demonstrated that levels of soluble proteins involved in neurodegenerative diseases are decreased.

关键词： diseases drug amyloid

The dual-action mechanism of Arabidopsis cryptochromes

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Journal of Integrative Plant Biology 2024年第5期66卷 883-896页

作者： Gao-Ping Qu Bochen Jiang Chentao Lin Basic Forestry and Plant proteomics Research Center Fujian Agriculture and Forestry UniversityFuzhou 350002China Department of Chemistry Department of Biochemistry and Molecular BiologyInstitute for Biophysical DynamicsThe University of ChicagoChicagoIL 60637USA

Photoreceptor cryptochromes (CRYs) mediate blue-light regulation of plant growth and development. It has been reported that Arabidopsis CRY1and CRY2 function by physically interacting with at least 84 proteins, including transcription factors or co-factors, chromatin regulators, splicing factors, messenger RNA methyltransferases, DNA repair proteins, E3 ubiquitin ligases, protein kinases and so on. Of these 84 proteins, 47 have been reported to exhibit altered binding affinity to CRYs in response to blue light, and 41 have been shown to exhibit condensation to CRY photobodies. The blue light-regulated composition or condensation of CRY complexes results in changes of gene expression and developmental programs. In this mini-review, we analyzed recent studies of the photoregulatory mechanisms of Arabidopsis CRY complexes and proposed the dual mechanisms of action, including the “Lock-and-Key” and the “Liquid-Liquid Phase Separation (LLPS)” mechanisms. The dual CRY action mechanisms explain, at least partially, the structural diversity of CRY-interacting proteins and the functional diversity of the CRY photoreceptors.

关键词： Arabidopsis blue light cryptochrome CRY1 CRY2 phaseseparation

STRAP binds to and promotes the repair of N1-methyldeoxyadenosine in DNA

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Chinese Chemical Letters 2024年第3期35卷 204-207页

作者： Meijuan Zhou Qian Liu Mengting Pan Ying Yang Xiaoxia Dai Changjun You State Key laboratory of Chemo/Biosensing and Chemometrics Hunan Provincial Key Laboratory of Biomacromolecular Chemical BiologyMolecular Science and Biomedicine LaboratoryCollege of Chemistry and Chemical EngineeringHunan UniversityChangsha 410082China

N1-methyladenosine(m1A)is an important RNA modification that functions in various biological processes by interacting with cellular ***,the binding proteins of N1-methyldeoxyadenosine(1mdA)in DNA remain largely ***,we employed a quantitative proteomics strategy to identify the potential binding proteins of 1mdA in human *** results revealed that serine–threonine kinase receptor-associated protein(STRAP)can bind to 1mdA-carrying *** further demonstrated that STRAP participates in alkylating agent-induced DNA damage response and can promote the repair of 1mdA embedded in ***,we investigated the effects of STRAP on 1mdA-induced perturbation in transcription using a shuttle vector-and next-generation sequencing-based assay,and found that STRAP is involved in the transcriptional bypass of 1mdA in human ***,our study revealed STRAP as a novel 1mdA-binding protein in human cells and provided new insight into the biological implications of STRAP and 1mdA modification in human diseases.

关键词： N1-methyldeoxyadenosine 1mdA-binding protein STRAP DNA repair Transcription

CRL2^(APPBP2)-mediated TSPYL2 degradation counteracts human mesenchymal stem cell senescence

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Science China(Life Sciences) 2024年第3期67卷 460-474页

作者： Daoyuan Huang Qian Zhao Kuan Yang Jinghui Lei Ying Jing Hongyu Li Chen Zhang Shuai Ma Shuhui Sun Yusheng Cai Guibin Wang Jing Qu Weiqi Zhang Si Wang Guang-Hui Liu Advanced Innovation Centerfor Human Brain Protection National Clinical Research Centerfor Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing 100053China State Key laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Aging Translational MedicineCenter International Centerfor Aging and CancerBejing Municipal GeriatricMedical Research CenterXuanwu HospitalCapital Medical UniversityBeijing 100053China State Key laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Beijing Institute for Stem Cell and Regenerative Medicine Beijing100101China CAS Key laboratory of Genomic and Precision Medicine Bejing Institute of Genomics and China National Center for BioinformationChinese Academy of SciencesBeijing 100101China Institute for Stem Cell and Regeneration CASBeijing 100101China The Fifth People's Hospital of Chongqing Chongqing 400062China Sino-Danish Cllege University of Chinese Academy of SciencesBeijing101408China National laboratory of Biomacromolecules CAS Center for Excelence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing100101China State Key laboratory of proteomics Beijing Proteome Research CenterNational Center for Protein Sciences(Beijing)Beijing Institute of LifeomicsBeijing 102206China

Cullin-RING E3 ubiquitin ligases(CRLs),the largest family of multi-subunit E3 ubiquitin ligases in eukaryotic cells,represent core cellular machinery for executing protein degradation and maintaining ***,we asked what roles Cullin proteins play in human mesenchymal stem cell(hMSC)homeostasis and *** this end,we conducted a comparative aging phenotype analysis by individually knocking down Cullin members in three senescence models:replicative senescent hMSCs,Hutchinson-Gilford Progeria Syndrome hMSCs,and Werner syndrome *** all family members,we found that CUL2 deficiency rendered hMSCs the most susceptible to *** investigate CUL2-specific underlying mechanisms,we then applied CRISPR/Cas9-mediated gene editing technology to generate CUL2-deficient human embryonic stem cells(hESCs).When we differentiated these into h MSCs,we found that CUL2 deletion markedly accelerates hMSC ***,we identified that CUL2 targets and promotes ubiquitin proteasome-mediated degradation of TSPYL2(a known negative regulator of proliferation)through the substrate receptor protein APPBP2,which in turn downregulates one of the canonical aging marker-P21^(waf1/cip1),and thereby delays *** work provides important insights into how CRL2^(APPBP2)-mediated TSPYL2 degradation counteracts hMSC senescence,providing a molecular basis for directing intervention strategies against aging and aging-related diseases.

关键词： Cullins stem cell senescence aging proteostasis ubiquitination APPBP2 TSPYL2

Proteo-transcriptomic profiles reveal key regulatory pathways and functions of LDHA in the ovulation of domestic chickens(Gallus gallus)

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Journal of Animal Science and Biotechnology 2024年第4期15卷 1449-1465页

作者： Ruixue Nie Wenhui Zhang Haoyu Tian Junying Li Yao Ling Bo Zhang Hao Zhang Changxin Wu State Key laboratory of Animal Biotech Breeding Beijing Key Laboratory for Animal Genetic ImprovementCollege of Animal Science and TechnologyChina Agricultural UniversityBeijing 100193China

Background In poultry, the smooth transition of follicles from the preovulatory-to-postovulatory phase impacts egg production in hens and can benefit the poultry industry. However, the regulatory mechanism underlying follicular ovulation in avians is a complex biological process that remains *** Critical biochemical events involved in ovulation in domestic chickens(Gallus gallus) were evaluated by transcriptomics, proteomics, and in vitro assays. Comparative transcriptome analyses of the largest preovulatory follicle(F1) and postovulatory follicle(POF1) in continuous laying(CL) and intermittent laying(IL) chickens indicated the greatest difference between CL_F1 and IL_F1, with 950 differentially expressed genes(DEGs), and the smallest difference between CL_POF1 and IL_POF1, with 14 DEGs. Additionally, data-independent acquisition proteomics revealed 252 differentially abundant proteins between CL_F1 and IL_F1. Perivitelline membrane synthesis, steroid biosynthesis, lysosomes, and oxidative phosphorylation were identified as pivotal pathways contributing to ovulation regulation. In particular, the regulation of zona pellucida sperm-binding protein 3, plasminogen activator, cathepsin A, and lactate dehydrogenase A(LDHA) was shown to be essential for ovulation. Furthermore, the inhibition of LDHA decreased cell viability and promoted apoptosis of ovarian follicles in *** This study reveals several important biochemical events involved in the process of ovulation, as well as crucial role of LDHA. These findings improve our understanding of ovulation and its regulatory mechanisms in avian species.

关键词： Chicken Data-independent acquisition proteomics LDHA Ovulation Regulatory mechanism Transcriptome

Gut commensal metabolite rhamnose promotes macrophages phagocytosis by activating SLC12A4 and protects against sepsis in mice

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Acta Pharmaceutica Sinica B 2024年第7期14卷 3068-3085页

作者： Dongping Li Rongjuan Wei Xianglong Zhang Shenhai Gong Meijuan Wan Fangzhao Wang Jiaxin Li Meiling Chen Ruofan Liu Yantong Wan Yinghao Hong Zhenhua Zeng Peng Gu Zhang Wang Kutty Selva Nandakumar Yong Jiang Hongwei Zhou Peng Chen Department of Pathophysiology Guangdong Provincial Key Laboratory of ProteomicsSchool of Basic Medical SciencesSouthern Medical UniversityGuangzhou 510000China Department of Critical Care Medicine Nanfang HospitalSouthern Medical UniversityGuangzhou 510000China Department of Gastroenterology Shenzhen HospitalSouthern Medical UniversityShenzhen 518000China dInstitute of Ecological Sciences School of Life SciencesSouth China Normal UniversityGuangzhou 510000China Department of Environmental and Biosciences School of BusinessInnovation and SustainabilityKristian IV’s vag 3Halmstad UniversityHalmstad 30004Sweden Microbiome Medicine Center Zhujiang HospitalSouthern Medical UniversityGuangzhou 510000China

Sepsis progression is significantly associated with the disruption of gut ***,the modulatory mechanisms of gut microbiota operating during sepsis are still ***,we investigated how gut commensals impact sepsis development in a pre-clinical *** ligation and puncture(CLP)surgery was used to establish polymicrobial sepsis in *** depleted of gut microbiota by an antibiotic cocktail(ABX)exhibited a significantly higher level of mortality than *** determined by metabolomics analysis,ABX treatment has depleted many metabolites,and subsequent supplementation with L-rhamnose(rhamnose,Rha),a bacterial carbohydrate metabolite,exerted profound immunomodulatory properties with a significant enhancement in macrophage phagocytosis,which in turn improved organ damage and ***,rhamnose binds directly to and activates the solute carrier family 12(potassium-chloride symporter),member 4(SLC12A4)in macrophages and promotes phagocytosis by activating the small G-proteins,Ras-related C3 botulinum toxin substrate1(Rac1)and cell division control protein 42 homolog(Cdc42).Interestingly,rhamnose has enhanced the phagocytosis capacity of macrophages from sepsis *** conclusion,by identifying SLC12A4 as the host interacting protein,we disclosed that the gut commensal metabolite rhamnose is a functional molecular that could promote the phagocytosis capacity of macrophages and protect the host against sepsis.

关键词： Gut microbiota Sepsis Rhamnose SLC12A4 GTP-Rac1 GTP-Cdc42 Macrophage Phagocytosis

Combined proteomic and metabolomic studies on the liver of Amur sturgeon Acipenser schrenckii under titanium dioxide nanoparticle exposure

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Journal of Oceanology and Limnology 2024年第3期42卷 1001-1015页

作者： Zhou ZHOU Ting LIU Jie KONG Zhenxing ZHAO Junquan ZHU Key laboratory of Aquacultural Biotechnology Ministry of Educationand Key Laboratory of Marine Biotechnology of Zhejiang ProvinceCollege of Marine SciencesNingbo UniversityNingbo 315000China Guizhou Fisheries Research Institute Guizhou Academy of Agriculture SciencesGuiyang 550000China

Nanomaterials,particularly titanium dioxide nanoparticles(TiO_(2)-NPs),are extensively utilized across various ***,their environmental release has raised concerns regarding their potential ecological and environmental *** reproductive toxicity of TiO_(2)-NPs in fish species has attracted considerable attention,yet conflicting research outcomes have been *** investigated the effects of TiO_(2)-NPs exposure on the liver of juvenile Amur sturgeon Acipenser schrenckii using label-free proteomic and untargeted metabolomic *** experiment included a control group and three groups exposed to different concentrations of TiO_(2)-NPs(low,TL;medium,TM;high,TH).Compared to the control group,9,19,and 25 proteins and 35,73,and 158 metabolites were differentially expressed in the TH,TM,and TL TiO_(2)-NP-exposed groups,*** differentially expressed genes(DEGs)were enriched in the Kyoto Encyclopedia for Genes and Genomes(KEGG)pathways related to glycolysis and ***,among the 126 correlated proteins,the most enriched pathways were associated with endocytosis and protein processing in the endoplasmic ***,syringic acid was significantly downregulated across all three TiO_(2)-NP-exposed *** obtain a comprehensive overview of the TiO_(2)-NP-induced expression changes,a co-regulated network of proteins and metabolites associated with TiO_(2)-NPs exposure was *** to TiO_(2)-NPs led to enrichment and alteration of pathways related to immune responses,including endocytosis,protein processing in the endoplasmic reticulum,and peroxisome proliferator-activated receptor(PPAR)*** conclusion,our findings indicate that exposure to TiO_(2)-NPs might disrupt glucose metabolism and induce immune responses,thus contributing to our understanding of the environmental impacts of nanomaterials and highlighting the need for further research and development of potential mitigation strategies.

关键词： TiO_(2)-nanoparticle exposure proteomics metabolomics glucose metabolism immune response