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The pathogenic mechanism of TAR DNA-binding protein 43(TDP-43)in amyotrophic lateral sclerosis

Neural Regeneration Research 2024年第4期19卷 800-806页

作者： Xinxin Wang Yushu Hu Renshi Xu Medical College of Nanchang University Department of Neurology Jiangxi Provincial People's HospitalThe First Affiliated Hospital of Nanchang Medical CollegeThe Clinical College of Nanchang Medical College

The onset of amyotrophic lateral sclerosis is usually characterized by focal death of both upper and/or lower motor neurons occurring in the motor cortex,basal ganglia,brainstem,and spinal cord,and commonly involves the muscles of the upper and/or lower extremities,and the muscles of the bulbar and/or respiratory regions.However,as the disease progresses,it affects the adjacent body regions,leading to generalized muscle weakness,occasionally along with memory,cognitive,behavioral,and language impairments;respiratory dysfunction occurs at the final stage of the disease.The disease has a complicated pathophysiology and currently,only riluzole,edaravone,and phenylbutyrate/taurursodiol are licensed to treat amyotrophic lateral sclerosis in many industrialized countries.The TAR DNA-binding protein 43 inclusions are observed in 97%of those diagnosed with amyotrophic lateral sclerosis.This review provides a preliminary overview of the potential effects of TAR DNAbinding protein 43 in the pathogenesis of amyotrophic lateral sclerosis,including the abnormalities in nucleoplasmic transport,RNA function,post-translational modification,liquid-liquid phase separation,stress granules,mitochondrial dysfunction,oxidative stress,axonal transport,protein quality control system,and non-cellular autonomous functions(e.g.,glial cell functions and prion-like propagation).

关键词： amyotrophic lateral sclerosis axonal transport liquid-liquid phase separation noncellular autonomous functions oxidative stress pathogenesis post-translational modification protein quality control system stress granules TAR DNA-binding protein 43(TDP-43)

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Blockade of the deubiquitinating enzyme USP48 degrades oncogenic HMGA2 and inhibits colorectal cancer invasion and metastasis

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1624-1643页

作者： Can Cheng Hanhui Yao Heng Li Jingwen Liu Zhengyi Liu Yang Wu Liang Zhu Hejie Hu Zhengdong Fang Liang Wu Department of General Surgery the First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei 230001China Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery the First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei 230001China Department of Comprehensive Surgery Anhui Provincial Cancer HospitalWest District of the First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei 230001China Anhui Provincial Hospital Health Management Center the First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei 230001China Department of Breast Surgery Henan Provincial People's HospitalPeople's Hospital of Zhengzhou UniversityPeople's Hospital of Henan UniversityZhengzhou 450003China

HMGA2,a pivotal transcription factor,functions as a versatile regulator implicated in the progression of diverse aggressive malignancies.In this study,mass spectrometry was employed to identify ubiquitin-specific proteases that potentially interact with HMGA2,and USP48 was identified as a deubiquitinating enzyme of HMGA2.The enforced expression of USP48 significantly increased HMGA2 protein levels by inhibiting its degradation,while the deprivation of USP48 promoted HMGA2 degradation,thereby suppressing tumor invasion and metastasis.We discovered that USP48 undergoes SUMOylation at lysine 258,which enhances its binding affinity to HMGA2.Through subsequent phenotypic screening of small molecules,we identified DUB-IN-2 as a remarkably potent pharmacological inhibitor of USP48.Interestingly,the small-molecule inhibitor targeting USP48 induces destabilization of HMGA2.Clinically,upregulation of USP48 or HMGA2 in cancerous tissues is indicative of poor prognosis for patients with colorectal cancer(CRC).Collectively,our study not only elucidates the regulatory mechanism of DUBs involved in HMGA2 stability and validates USP48 as a potential therapeutic target for CRC,but also identifies DUB-IN-2 as a potent inhibitor of USP48 and a promising candidate for CRC treatment.

关键词： Colorectal cancer Invasion and metastasis post-translational modification Ubiquitination SUMOylation USP48 HMGA2 Specific inhibitors

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post-translational modification of Parkin and its research progress in cancer

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Cancer Communications 2019年第1期39卷 655-664页

作者： Dan Ding Xiang Ao Ying Liu Yuan-Yong Wang Hong-Ge Fa Meng-Yu Wang Yu-Qi He Jian-Xun Wang School of Basic Medical Sciences Qingdao UniversityNo.38 Dengzhou RoadShibei DistrictQingdao 266000ShandongP.R.China Center for Regenerative Medicine Institute for Translational MedicineCollege of MedicineQingdao UniversityQingdao 266000ShandongP.R.China Department of Thoracic Surgery Affiliated Hospital of Qingdao UniversityQingdao 266000ShandongP.R.China Department of Gastroenterology The Seventh Medical Center of PLA General HospitalBeijing 100700China

Clinical practice has shown that Parkin is the major causative gene found in an autosomal recessive juvenile parkin-sonism(AR-JP)via Parkin mutations and that the Parkin protein is the core expression product of the Parkin gene,which itself belongs to an E3 ubiquitin ligase.Since the discovery of the Parkin gene in the late 1990s,researchers in many countries have begun extensive research on this gene and found that in addition to AR-JP,the Parkin gene is associated with many diseases,including type 2 diabetes,leprosy,Alzheimer’s,autism,and cancer.Recent studies have found that the loss or dysfunction of Parkin has a certain relationship with tumorigenesis.In general,the Parkin gene,a well-established tumor suppressor,is deficient and mutated in a variety of malignancies.Parkin overexpres-sion inhibits tumor cell growth and promotes apoptosis.However,the functions of Parkin in tumorigenesis and its regulatory mechanisms are still not fully understood.This article describes the structure,functions,and post-transla-tional modifications of Parkin,and summarizes the recent advances in the tumor suppressive function of Parkin and its underlying mechanisms.

关键词： Parkin E3 ubiquitin ligase Cancer post-translational modification Parkin/PTEN-induced kinase 1(PINK1) NIP3-like protein X Ubiquitination Sumoylation Neddylation Phosphorylation

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Role of post-translational modification of the Y box binding protein 1 in human cancers

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Genes & Diseases 2015年第3期2卷 240-246页

作者： Lakshmi Prabhu Antja-Voy Hartley Matthew Martin Fadumo Warsame Emily Sun Tao Lu Department of Pharmacology and Toxicology Indiana University School of Medicine635 Barnhill DriveIndianapolisIN 46202USA Department of Biochemistry and Molecular Biology Indiana University School of Medicine635 Barnhill DriveIndianapolisIN 46202USA Department of Medical and Molecular Genetics 975 West Walnut StreetMedical Research and Library BuildingIndianapolisIN 46202USA

Y box binding protein-1(YBX1)belongs to a DNA-and RNA-binding family of transcription factors,containing the highly conserved cold shock domain(CSD).YBX1 is involved in a number of cellular functions including transcription,translation,DNA damage repair etc.,and it is upregulated during times of environmental stress.YBX1 is localized in both the cytoplasm and the nucleus.There,its nuclear translocation is observed in a number of cancers and is associated with poor prognosis and disease progression.Additionally,YBX1 expression is upregulated in a variety of cancers,pointing towards its role as a potential oncogene.Under certain circumstances,YBX1 also promotes the expression of multidrug resistance 1(MDR1)gene,which is involved in the development of drug resistance.Thus,it is critical to understand the mechanism of YBX1 regulation and its downstream effects on promoting cancer development.A number of recent studies have highlighted the mechanisms of YBX1 regulation.Mass spectrometric analyses have reported several post-translational modifications that possibly play an important role in modulating YBX1 function.Phosphorylation is the most widely occurring post-translational modification in YBX1.In vivo analyses of sites like S102 and more recently,S165 illustrate the relationship of post-translational regulation of YBX1 in promoting cell proliferation and tumor growth.This review provides a comprehensive and up-to-date account of post-translational modifications identified in YBX1.This knowledge is a key in allowing us to better understand the mechanism of YBX1 regulation,which will aid in development of novel therapeutic strategies to target YBX1 in many types of cancer in the future.

关键词： Cancer Cold shock domain Phosphorylation post-translational modification Y box binding protein 1

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Functions and mechanisms of protein lysine butyrylation(Kbu):Therapeutic implications in human diseases

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Genes & Diseases 2023年第6期10卷 2479-2490页

作者： Qianqian Xue Yanyan Yang Hong Li Xiaoxin Li Lu Zou Tianxiang Li Huibo Ma Hongzhao Qi Jianxun Wang Tao Yu Institute for translational Medicine The Affiliated Hospital of Qingdao UniversityQingdaoShandong 266000China Department of Immunology School of Basic MedicineQingdao UniversityQingdaoShandong 266021China Clinical Laboratory Central Laboratory.The Affiliated Qingdao Hiser Hospital of Qingdao UniversityQingdaoShandong 266000China Department of Vascular Surgery The Affiliated Hospital of Qingdao UniversityQingdaoShandong 266000China Department of Cardiac Ultrasound The Affiliated Hospital of Qingdao UniversityQingdaoShandong 266000China

post-translational modifications(PTM)are covalent modifications of proteins or peptides caused by proteolytic cleavage or the attachment of moieties to one or more amino acids.PTMs play essential roles in biological function and regulation and have been linked with several diseases.modifications of protein acylation(Kac),a type of PTM,are known to induce epigenetic regulatory processes that promote various diseases.Thus,an increasing number of studies focusing on acylation modifications are being undertaken.Butyrylation(Kbu)is a new acylation process found in animals and plants.Kbu has been recently linked to the onset and progression of several diseases,such as cancer,cardiovascular diseases,diabetes,and vascular dementia.Moreover,the mode of action of certain drugs used in the treatment of lymphoma and colon cancer is based on the regulation of butyrylation levels,suggesting that butyrylation may play a therapeutic role in these diseases.In addition,butyrylation is also commonly involved in rice gene expression and thus plays an important role in the growth,development,and metabolism of rice.The tools and analytical methods that could be utilized for the prediction and detection of lysine butyrylation have also been investigated.This study reviews the potential role of histone Kbu,as well as the mechanisms underlying this process.It also summarizes various enzymes and analytical methods associated with Kbu,with the goal of providing new insights into the role of Kbu in gene regulation and diseases.

关键词： Butyrylation Gene regulation Histone post-translational modification Target treatment

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PRMT6 promotes tumorigenicity and cisplatin response of lung cancer through triggering 6PGD/ENO1 mediated cell metabolism

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Acta Pharmaceutica Sinica B 2023年第1期13卷 157-173页

作者： Mingming Sun Leilei Li Yujia Niu Yingzhi Wang Qi Yan Fei Xie Yaya Qiao Jiaqi Song Huanran Sun Zhen Li Sizhen Lai Hongkai Chang Han Zhang Jiyan Wang Chenxin Yang Huifang Zhao Junzhen Tan Yanping Li Shuangping Liu Bin Lu Min Liu Guangyao Kong Yujun Zhao Chunze Zhang Shu-Hai Lin Cheng Luo Shuai Zhang Changliang Shan State Key Laboratory of Medicinal Chemical Biology College of Pharmacy and Tianjin Key Laboratory of Molecular Drug ResearchNankai UniversityTianjin 300350China Biomedical translational Research Institute Jinan UniversityGuangzhou 510632China State Key Laboratory of Cellular Stress Biology Innovation Center for Cell Signaling NetworkSchool of Life SciencesXiamen UniversityXiamen 361102China School of Integrative Medicine Tianjin University of Traditional Chinese MedicineTianjin 301617China Department of Pathology and Institute of Precision Medicine Jining Medical UniversityJining 272067China Department of Pathology Medical SchoolDalian UniversityDalian 116622China Department of Biochemistry and Molecular Biology School of Basic Medical SciencesHengyang Medical SchoolUniversity of South ChinaHengyang 421001China School of Laboratory Medicine and Life Sciences Wenzhou Medical UniversityWenzhou 325035China Institute of Biomedical Sciences Shandong Provincial Key Laboratory of Animal Resistance BiologyCollaborative Innovation Center of Cell Biology in Universities of ShandongCollege of Life SciencesShandong Normal UniversityJinan 250014China National Local Joint Engineering Research Center of Biodiagnostics and Biotherapy the Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'an 710004China State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Department of Colorectal Surgery Tianjin Union Medical Center Nankai UniversityTianjin 300121China

Metabolic reprogramming is a hallmark of cancer,including lung cancer.However,the exact underlying mechanism and therapeutic potential are largely unknown.Here we report that protein arginine methyltransferase 6(PRMT6)is highly expressed in lung cancer and is required for cell metabolism,tumorigenicity,and cisplatin response of lung cancer.PRMT6 regulated the oxidative pentose phosphate pathway(PPP)flux and glycolysis pathway in human lung cancer by increasing the activity of 6-phosphogluconate dehydrogenase(6PGD)and a-enolase(ENO1).Furthermore,PRMT6 methylated R324 of 6PGD to enhancing its activity;while methylation at R9 and R372 of ENO1 promotes formation of active ENO1 dimers and 2-phosphoglycerate(2-PG)binding to ENO1,respectively.Lastly,targeting PRMT6 blocked the oxidative PPP flux,glycolysis pathway,and tumor growth,as well as enhanced the antitumor effects of cisplatin in lung cancer.Together,this study demonstrates that PRMT6 acts as a posttranslational modification(PTM)regulator of glucose metabolism,which leads to the pathogenesis of lung cancer.It was proven that the PRMT6-6PGD/ENO1 regulatory axis is an important determinant of carcinogenesis and may become a promising cancer therapeutic strategy.

关键词： Lung cancer Metabolic reprogramming post-translational modification PRMT6 Pentose phosphate pathway flux Glycolysis 6-Phospho-gluconate dehydrogenase a-enolase ENO1

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A Review of Machine Learning and Algorithmic Methods for Protein Phosphorylation Site Prediction

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Genomics, Proteomics & Bioinformatics 2023年第6期21卷 1266-1285页

作者： Farzaneh Esmaili Mahdi Pourmirzaei Shahin Ramazi Seyedehsamaneh Shojaeilangari Elham Yavari Department of Information Technology Tarbiat Modares UniversityTehran 14115-111Iran Department of Biophysics Faculty of Biological SciencesTarbiat Modares UniversityTehran 14115-111Iran Biomedical Engineering Group Department of Electrical Engineering and Information TechnologyIranian Research Organization for Science and Technology(IROST)Tehran 33535-111Iran

post-translational modifications(PTMs)have key roles in extending the functional diversity of proteins and,as a result,regulating diverse cellular processes in prokaryotic and eukaryotic organisms.Phosphorylation modification is a vital PTM that occurs in most proteins and plays a significant role in many biological processes.Disorders in the phosphorylation process lead to multiple diseases,including neurological disorders and cancers.The purpose of this review is to organize this body of knowledge associated with phosphorylation site(p-site)prediction to facilitate future research in this field.At first,we comprehensively review all related databases and introduce all steps regarding dataset creation,data preprocessing,and method evaluation in p-site prediction.Next,we investigate p-site prediction methods,which are divided into two computational groups:algorithmic and machine learning(ML).Additionally,it is shown that there are basically two main approaches for p-site prediction by ML:conventional and end-to-end deep learning methods,both of which are given an overview.Moreover,this review introduces the most important feature extraction techniques,which have mostly been used in p-site prediction.Finally,we create three test sets from new proteins related to the released version of the database of protein post-translational modifications(dbPTM)in 2022 based on general and human species.Evaluating online p-site prediction tools on newly added proteins introduced in the dbPTM 2022 release,distinct from those in the dbPTM 2019 release,reveals their limitations.In other words,the actual performance of these online p-site prediction tools on unseen proteins is notably lower than the results reported in their respective research pape.

关键词： Phosphorylation Machinelearning Deep learning post-translational modification Database

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Current understanding of the cGAS-STING signaling pathway: Structure, regulatory mechanisms, and related diseases

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Zoological Research 2023年第1期44卷 183-218页

作者： Jing Pan Chen-Jie Fei Yang Hu Xiang-Yu Wu Li Nie Jiong Chen State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products Ningbo UniversityNingboZhejiang 315211China Laboratory of Biochemistry and Molecular Biology School of Marine SciencesMeishan CampusNingbo UniversityNingboZhejiang 315832China Zhejiang Key Laboratory of Marine Bioengineering Ningbo UniversityNingboZhejiang 315832China

The innate immune system protects the host from external pathogens and internal damage in various ways. The cGAS-STING signaling pathway,comprised of cyclic GMP-AMP synthase(cGAS),stimulator of interferon genes(STING), and downstream signaling adaptors, plays an essential role in protective immune defense against microbial DNA and internal damaged-associated DNA and is responsible for various immune-related diseases.After binding with DNA, cytosolic cGAS undergoes conformational change and DNA-linked liquid-liquid phase separation to produce 2’3’-c GAMP for the activation of endoplasmic reticulum(ER)-localized STING. However, further studies revealed that cGAS is predominantly expressed in the nucleus and strictly tethered to chromatin to prevent binding with nuclear DNA, and functions differently from cytosoliclocalized cGAS. Detailed delineation of this pathway,including its structure, signaling, and regulatory mechanisms, is of great significance to fully understand the diversity of cGAS-STING activation and signaling and will be of benefit for the treatment of inflammatory diseases and cancer. Here, we review recent progress on the above-mentioned perspectives of the cGAS-STING signaling pathway and discuss new avenues for further study.

关键词： cGAS STING Structure Signaling post-translational modification Diseases

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Influence of Sox protein SUMOylation on neural development and regeneration

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Neural Regeneration Research 2022年第3期17卷 477-481页

作者： Kun-Che Chang Department of Ophthalmology Louis J.Fox Center for Vision RestorationUniversity of Pittsburgh School of MedicinePittsburghPAUSA

SRY-related HMG-box(Sox) transcription factors are known to regulate central nervous system development and are involved in several neurological diseases.post-translational modification of Sox proteins is known to alter their functions in the central nervous system.Among the different types of post-translational modification,small ubiquitin-like modifier(SUMO) modification of Sox proteins has been shown to modify their transcriptional activity.Here,we review the mechanisms of three Sox proteins in neuronal development and disease,along with their transcriptional changes under SUMOylation.Across three species,lysine is the conserved residue for SUMOylation.In Drosophila,SUMOylation of Sox N plays a repressive role in transcriptional activity,which impairs central nervous system development.However,de SUMOylation of Sox E and Sox11 plays neuroprotective roles,which promote neural crest precursor formation in Xenopus and retinal ganglion cell differentiation as well as axon regeneration in the rodent.We further discuss a potential translational therapy by SUMO site modification using AAV gene transduction and Clustered regularly interspaced short palindromic repeats-Cas9 technology.Understanding the underlying mechanisms of Sox SUMOylation,especially in the rodent system,may provide a therapeutic strategy to address issues associated with neuronal development and neurodegeneration.

关键词： axon regeneration neural development neurological disorder neuroprotection post-translational modification small ubiquitin-like modifier Sox transcription factor SUMOylation

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Diagnostic and Prognostic Value of Protein post-translational modifications in Hepatocellular Carcinoma

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Journal of Clinical and translational Hepatology 2023年第5期11卷 1192-1200页

作者： Jing Wang Fangfang Wang Ning Wang Mei-Yin Zhang Hui-Yun Wang Guo-Liang Huang Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics The First Dongguan Affiliated HospitalGuangdong Medical UniversityDongguanGuangdongChina China-America Cancer Research Institute Key Laboratory for Epigenetics of Dongguan CityGuangdong Medical UniversityDongguanGuangdongChina State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineSun Yat-Sen University Cancer CenterGuangzhouGuangdongChina

Hepatocellular carcinoma(HCC)is a common malignant tumor with high incidence and cancer mortality worldwide.post-translational modifications(PTMs)of proteins have a great impact on protein function.Almost all proteins can undergo PTMs,including phosphorylation,acetylation,methylation,glycosylation,ubiquitination,and so on.Many studies have shown that PTMs are related to the occurrence and development of cancers.The findings provide novel therapeutic targets for cancers,such as glypican-3 and mucin-1.Other clinical implications are also found in the studies of PTMs.Diagnostic or prognostic value,and response to therapy have been identified.In HCC,it has been shown that glycosylated alpha-fetoprotein(AFP)has a higher detection rate for early liver cancer than conventional AFP.In this review,we mainly focused on the diagnostic and prognostic value of PTM,in order to provide new insights into the clinical implication of PTM in HCC.

关键词： Diagnosis Hepatocellular carcinoma post-translational modification Prognosis

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