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Choline dehydrogenase interacts with sqstm1 to activate mitophagy and promote coelomocyte survival in Apostichopus japonicus following Vibrio splendidus infection

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动物学研究(英文) 2023年第5期44卷 905-918页

作者： Lian-Lian Sun Ying-Fen Dai Mei-Xiang You Cheng-Hua Li State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products Ningbo UniversityNingboZhejiang 315211China Laboratory for Marine Fisheries Science and Food Production Processes Qingdao National Laboratory for Marine Science and TechnologyQingdaoShandong 266071China

Previous studies have shown that Vibrio splendidus infection causes mitochondrial damage in Apostichopus japonicus coelomocytes,leading to the production of excessive reactive oxygen species(ROS)and irreversible apoptotic cell death.Emerging evidence suggests that mitochondrial autophagy(mitophagy)is the most effective method for eliminating damaged mitochondria and ROS,with choline dehydrogenase(CHDH)identified as a novel mitophagy receptor that can recognize non-ubiquitin damage signals and microtubule-associated protein 1 light chain 3(LC3)in vertebrates.However,the functional role of CHDH in invertebrates is largely unknown.In this study,we observed a significant increase in the mRNA and protein expression levels of A.japonicus CHDH(AjCHDH)in response to V.splendidus infection and lipopolysaccharide(LPS)challenge,consistent with changes in mitophagy under the same conditions.Notably,AjCHDH was localized to the mitochondria rather than the cytosol following V.splendidus infection.Moreover,AjCHDH knockdown using si RNA transfection significantly reduced mitophagy levels,as observed through transmission electron microscopy and confocal microscopy.Further investigation into the molecular mechanisms underlying CHDH-regulated mitophagy showed that AjCHDH lacked an LC3-interacting region(LIR)for direct binding to LC3 but possessed a FB1 structural domain that binds to sqstm1.The interaction between AjCHDH and sqstm1 was further confirmed by immunoprecipitation analysis.Furthermore,laser confocal microscopy indicated that sqstm1 and LC3 were recruited by AjCHDH in coelomocytes and HEK293T cells.In contrast,AjCHDH interference hindered sqstm1 and LC3 recruitment to the mitochondria,a critical step in damaged mitochondrial degradation.Thus,AjCHDH interference led to a significant increase in both mitochondrial and intracellular ROS,followed by increased apoptosis and decreased coelomocyte survival.Collectively,these findings indicate that AjCHDH-mediated mitophagy plays a crucial role in coelomocyte survival in A.japon

关键词： Choline dehydrogenase Mitophagy sqstm1 Microtubule-associated protein 1 light chain 3 Apostichopus japonicus

Impairment of autophagy promotes human conjunctival fibrosis and pterygium occurrence via enhancing the sqstm1-NF-κB signaling pathway

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分子细胞生物学报:英文版 2023年第1期15卷 41-57页

作者： Qin He Yiting Cai Jiani Huang Xiaoying He Wei Han Wei Chen Department of Ophthalmology The First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou 310003China Institute of Immunology School of MedicineZhejiang UniversityHangzhou 310058China Eye Center of the Second Affiliated Hospital School of MedicineZhejiang UniversityHangzhou 310009China

Pterygium is a common ocular disease with a high recurrence rate,characterized by hyperplasia of subconjunctival fibrovascular tissue.Autophagy,an important process to maintain cellular homeostasis,participates in the pathogenic fibrosis of different organs.However,the exact role of autophagy in pterygium pathogenesis remains unknown.Here,we found that autophagic activity was decreased in human pterygium tissues compared with adjacent normal conjunctival tissues.The in vitro model of fibrosis was successfully established using human primary conjunctival fibroblasts(ConFB)treated with transforming growth factor-β1(TGF-β1),evidenced by increased fibrotic level and strong proliferative and invasive capabilities.The autophagic activity was suppressed during TGF-β1-or ultraviolet-induced fibrosis of ConFB.Activating autophagy dramatically retarded the fibrotic progress of ConFB,while blocking autophagy exacerbated this process.Furthermore,sqstm1,the main cargo receptor of selective autophagy,was found to significantly promote the fibrosis of ConFB through activating the PKCι-NF-κB signaling pathway.Knockdown of sqstm1,PKCι,or p65 in ConFB delayed TGF-β1-induced fibrosis.Overexpression of sqstm1 drastically abrogated the inhibitory effect of rapamycin or serum starvation on TGF-β1-induced fibrosis.Collectively,our data suggested that autophagy impairment of human ConFB facilitates fibrosis via activating the sqstm1-PKCι-NF-κB signaling cascades.This work was contributory to elucidating the mechanism of autophagy underlying pterygium occurrence.

关键词： pterygium autophagy fibrosis sqstm1 NF-κB

Clinical significance of sqstm1/P62 and nuclear factor-κB expression in pancreatic carcinoma

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World Journal of Gastrointestinal Oncology 2020年第7期12卷 719-731页

作者： Zhao-Yang Zhang Sen Guo Rui Zhao Zhi-Peng Ji Zhuo-Nan Zhuang Department of Emergency Surgery Qilu HospitalShandong UniversityJinan 250012Shandong ProvinceChina Department of General Surgery Qilu HospitalShandong UniversityJinan 250012Shandong ProvinceChina Department of General Surgery Second Affiliated Hospital of Shandong UniversityJinan 250033Shandong ProvinceChina Department of Gastrointestinal Surgery Beijing Tsinghua Changgung HospitalSchool of Clinical MedicineTsinghua UniversityBeijing 102200China

BACKGROUND Overexpression of sqstm1(sequestosome 1,P62)and nuclear factor-κB(NF-κB)plays an important role in the invasion and metastasis of a variety of malignant tumors.AIM To explore the expression of P62 and NF-κB in pancreatic cancer and their relationship with clinicopathological features.METHODS The expression levels of P62 and NF-κB were analyzed by immunohistochemistry with a tissue chip containing 40 cases of human pancreatic carcinoma.Then we analyzed the correlation among P62 expression,phospho-P65 expression,and clinicopathological features of pancreatic carcinoma samples.RESULTS P62 expression was mainly observed in the cytoplasm of pancreatic carcinoma cells.Phosphorylated P65(phospho-P65)was mainly expressed in the nucleus and cytoplasm of pancreatic carcinoma cells.There was a significant difference in P62 expression among T stages.And a significant difference in phosphor-P65 expression among pathology types was noted.In the cases with strongly positive P62 expression,significant differences were found in age.And there were significant differences in T stage and tumor-node-metastasis stage in the cases with strongly positive phosphor-P65 expression.CONCLUSION In pancreatic carcinoma,P62 expression is significantly correlated with T stage.It may be a valuable malignant indicator for human pancreatic carcinoma.

关键词： Pancreatic carcinoma Phosphorylated P65 P62 sqstm1 Nuclear factor-κB Malignant

sqstm1蛋白在嗜肺军团菌感染RAW264.7细胞自噬中的作用机制

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山东大学学报（医学版） 2023年第6期61卷 10-21页

作者：郑荣慧李攀曹秀琴贺瑞霞陈民佳陈海霞杨志伟宁夏医科大学基础医学院病原生物学与免疫学系宁夏银川750004 银川市第三人民医院检验科宁夏银川750001 宁夏医科大学生育力保持省部级共建教育部重点实验室宁夏银川750004

目的以sqstm1蛋白(P62)基因敲除及过表达的RAW264.7小鼠巨噬细胞为研究对象,建立嗜肺军团菌感染巨噬细胞模型,观察细胞内细菌增殖情况以及自噬流和自噬小体的变化,检测自噬相关因子表达水平变化,探讨P62在嗜肺军团菌感染RAW264.7巨噬细... 详细信息

目的以sqstm1蛋白(P62)基因敲除及过表达的RAW264.7小鼠巨噬细胞为研究对象,建立嗜肺军团菌感染巨噬细胞模型,观察细胞内细菌增殖情况以及自噬流和自噬小体的变化,检测自噬相关因子表达水平变化,探讨P62在嗜肺军团菌感染RAW264.7巨噬细胞自噬中的作用机制。方法嗜肺军团菌以感染复数10、50和100感染RAW264.7巨噬细胞组、KO-P62细胞组、OE-P62细胞组,同时以未加嗜肺军团菌感染作为对照组;细菌增殖实验观察嗜肺军团菌在巨噬细胞内的增殖情况;透射电镜观察嗜肺军团菌与细胞共培养12 h时RAW264.7巨噬细胞组、KO-P62细胞组、OE-P62细胞组的自噬小体、自噬溶酶体及相关细胞器等超微结构;pmCherry-C1-EGFP-LC3B双荧光指示系统检测巨噬细胞自噬流的变化;采用免疫印迹试验(Western blotting)及实时荧光定量(RT-qPCR)法检测RAW264.7巨噬细胞组、KO-P62细胞组、OE-P62细胞组P62、自噬相关基因AMBRA1、溶酶体关联膜蛋白2(LAMP2)、自噬相关蛋白5(Atg5)、自噬效应蛋白1(Beclin1)、自噬微管相关蛋白轻链3(LC3B)的表达水平。结果细菌增殖实验检测在RAW264.7细胞组内嗜肺军团菌的数量随着时间的增长逐渐增长,在KO-P62细胞组及OE-P62细胞组内嗜肺军团菌的数量随着时间的增长均逐渐减少;透射电镜可观察到嗜肺军团菌感染RAW264.7细胞组后,自噬小体及自噬溶酶体减少,与RAW264.7细胞组相比,KO-P62细胞组及OE-P62细胞组自噬小体及自噬溶酶体均增多;pmCherry-C1-EGFP-LC3B双荧光指示系统检测自噬流结果显示,嗜肺军团菌感染RAW264.7细胞组,自噬流均减弱,KO-P62细胞组及OE-P62细胞组自噬流增加;Western blotting及RT-qPCR结果显示,与RAW264.7细胞组相比:KO-P62细胞组Beclin1先升高后降低,P62基本不表达,LC3Ⅱ/Ⅰ比值、AMBRA1、LAMP2及Atg5蛋白表达均明显升高,差异有统计学意义(P1先降低后升高,P62、AMBRA1、LAMP2、Atg5及LC3Ⅱ/Ⅰ比值均明显上调,差异有统计学意义(P1信号通路有关。

关键词：嗜肺军团菌感染巨噬细胞 sqstm1 自噬

SHMT2结合并上调sqstm1促进结肠癌细胞增殖

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医药导报 2023年第6期42卷 814-818页

作者：陈前智沈娜李雪芹华中科技大学同济医学院附属协和医院乳腺甲状腺外科武汉430022

目的探索SHMT2调控结肠癌细胞增殖的分子机制。方法通过免疫组化染色及生物信息分析来验证SHMT2在结肠癌组织中的表达和作用,通过细胞克隆形成实验检测SHMT2对结肠癌细胞增殖能力的影响,利用免疫共沉淀法、质粒转染、蛋白印迹实验等验证... 详细信息

目的探索SHMT2调控结肠癌细胞增殖的分子机制。方法通过免疫组化染色及生物信息分析来验证SHMT2在结肠癌组织中的表达和作用,通过细胞克隆形成实验检测SHMT2对结肠癌细胞增殖能力的影响,利用免疫共沉淀法、质粒转染、蛋白印迹实验等验证SHMT2在结肠癌中的作用机制。结果免疫组化染色揭示SHMT2蛋白在结肠癌肿瘤组织中显著高表达,通过生信分析发现SHMT2 mRNA水平与结肠癌的不良预后相关,在细胞实验中发现SHMT2低表达或者SHMT2抑制剂可显著抑制结肠癌细胞增殖,其作用机制可能是SHMT2通过与sqstm1结合并上调其蛋白水平来促进结肠癌细胞增殖。结论该研究发现SHMT2-sqstm1信号轴对结肠癌细胞增殖的关键调控作用,为结肠癌相关分子机制研究提供了新的线索和方向。

关键词：结肠癌丝氨酸羟甲基转移酶2(SHMT2) SHMT2抑制剂 sqstm1 增殖

sqstm1在甲状腺乳头状癌中的表达及其对甲状腺乳头状癌侵袭、迁移和增殖能力的影响

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中华医学杂志 2021年第2期101卷 147-151页

作者：余芳沁刘晨光马润声张乐乐杜公博牛东鹏殷德涛郑州大学第一附属医院甲状腺外科河南省高等学校临床医学重点学科开放实验室郑州450052

目的探究sqstm1在甲状腺乳头状癌中的表达及其对甲状腺乳头状癌细胞TPC-1侵袭和迁移能力的影响。方法采集2019年4至6月郑州大学第一附属医院收治的21例甲状腺乳头状癌患者切除手术的癌组织和癌旁组织,通过逆转录-聚合酶链反应(RT-qPCR)... 详细信息

目的探究sqstm1在甲状腺乳头状癌中的表达及其对甲状腺乳头状癌细胞TPC-1侵袭和迁移能力的影响。方法采集2019年4至6月郑州大学第一附属医院收治的21例甲状腺乳头状癌患者切除手术的癌组织和癌旁组织,通过逆转录-聚合酶链反应(RT-qPCR)方法检测组织中sqstm1的表达情况;通过慢病毒转染在TPC-1细胞中构建sqstm1缺失细胞系sqstm1-KD-TPC-1,RT-qPCR从基因水平检测sqstm1在TPC-1和sqstm1-KD-TPC-1细胞中的表达;transwell法检测sqstm1敲低前后TPC-1侵袭和迁移的变化情况;MTT和平板克隆形成实验检测sqstm1敲低后TPC-1细胞增殖能力的变化;通过RT-qPCR检测增殖相关蛋白的表达情况,从基因水平进一步验证肿瘤细胞对增殖能力的影响。结果甲状腺乳头状癌组织中sqstm1的表达明显高于正常癌旁组织,有76.2%(16/21)的患者mRNA呈现高表达;敲低sqstm1明显抑制肿瘤增殖、侵袭和迁移的能力,且增殖相关蛋白表达明显减小(P均1),表明sqstm1参与增殖相关通路机制的调控。结论sqstm1在甲状腺乳头状癌细胞株TPC-1中明显促进细胞侵袭、迁移和增殖,可能是潜在的基因治疗靶点。

关键词： sqstm1 甲状腺乳头状癌侵袭迁移增殖

基于p62/sqstm1-luciferase的细胞自噬水平检测方法的建立及鉴定

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中国生物工程杂志 2016年第1期36卷 55-62页

作者：赵远波洪杜北琦陈英玉贵州医科大学生物与工程学院贵阳550025 北京大学基础医学院北京100191 北京大学人类疾病基因研究中心北京100191

自噬是细胞依赖溶酶体对大批量蛋白质和细胞器进行降解的一条重要途径。目前已发现很多基因和自噬过程相关,但是对自噬过程的分子机制尚未明了,因此建立自噬检测方法进行新的自噬相关分子的鉴定显得尤为重要。构建了选择性自噬底物p62/S... 详细信息

自噬是细胞依赖溶酶体对大批量蛋白质和细胞器进行降解的一条重要途径。目前已发现很多基因和自噬过程相关,但是对自噬过程的分子机制尚未明了,因此建立自噬检测方法进行新的自噬相关分子的鉴定显得尤为重要。构建了选择性自噬底物p62/sqstm1(Sequestosome 1)和萤火虫荧光素酶报告基因融合表达的重组质粒,通过检测细胞内荧光素酶的活性来分析细胞自噬流,建立了一个简单且适用于通量化筛选的细胞自噬检测方法,为进一步的高通量自噬分子的筛选奠定了基础。

关键词：自噬 sqstm1 荧光素酶 p62

膀胱尿路上皮癌中LC3B与sqstm1的表达及其临床意义

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临床与实验病理学杂志 2021年第12期37卷 1483-1485页

作者：徐芳华巢海潮邓雷弘南方医科大学附属萍乡医院病理科萍乡337000 南昌大学第二附属医院泌尿外科南昌330006 南昌大学第一附属医院超声医学科南昌330006

目的探讨微管相关蛋白1轻链3β(microtubule-associated protein 1 light chain 3β,LC3B)及选择性自噬接头蛋白1(sequestosome 1,sqstm1)在膀胱尿路上皮癌组织中的表达及其临床意义。方法采用免疫组化MaxVision法检测LC3B与sqstm1在48例膀胱尿路上皮癌组织及7例正常膀胱黏膜组织中的表达,并分析其表达与膀胱尿路上皮癌临床病理特征的关系。结果LC3B、sqstm1在膀胱尿路上皮癌中的阳性率高于正常组织,差异有统计学意义(χ^(2)=28.187,P1;χ^(2)=31.850,P1)。sqstm1表达与膀胱尿路上皮癌临床分期、淋巴结转移及肿瘤分化程度明显相关(χ^(2)=13.05,P=0.0003;χ^(2)=5.035,P=0.025;χ^(2)=11.161,P=0.0008)。结论LC3B与sqstm1在膀胱尿路上皮癌组织中均呈高表达,与膀胱尿路上皮癌的进展密切相关,有望成为膀胱尿路上皮癌诊疗的新靶点及生物学标志物。

关键词：膀胱肿瘤尿路上皮癌 LC3B sqstm1 临床病理学特征

p62/sqstm1 mRNA及蛋白质表达水平与系统性红斑狼疮相关性研究

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中华风湿病学杂志 2013年第11期17卷 734-737页

作者：罗雄燕杨明辉夏艳辉余成秀邹倩向阳刘毅袁国华四川大学华西医院风湿免疫科成都610041 川北医学院附属医院风湿免疫研究所风湿科湖北民族学院民大附属医院

目的检测p62/sqstm1在系统性红斑狼疮（SLE）中的表达情况,明确自噬相关基因p62/sqstm1与SLE发病的关系.方法应用实时定量聚合酶链反应技术检测p62/sqstm1 mRNA在136例SLE患者和25名健康对照组的表达水平,应用蛋白印迹法检测SLE患者中... 详细信息

目的检测p62/sqstm1在系统性红斑狼疮（SLE）中的表达情况,明确自噬相关基因p62/sqstm1与SLE发病的关系.方法应用实时定量聚合酶链反应技术检测p62/sqstm1 mRNA在136例SLE患者和25名健康对照组的表达水平,应用蛋白印迹法检测SLE患者中p62/sqstm1蛋白表达水平.2组计量资料比较采用t检验,计数资料比较采用x2检验.结果 p62/sqstm1 mRNA在136例SLE患者表达上调,其△Ct值为4.3±1.4,低于健康对照组的5.0±1.8（t=-1.990 6,P=0.048）（△Ct值越小,表达量越大）.SLE患者中p62/sqstm1蛋白质表达水平显著高于健康对照组（0.070 ±0.008和0.046 ±0.007,t=5.943,P=0.001）.结论自噬相关基因p62/sqstm1表达上调促进SLE的发生.

关键词：红斑狼疮,系统性聚合酶链反应 p62 sqstm1