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SUb1 promotes colorectal cancer metastasis by activating nf-κb signaling via UbR5-mediated ubiquitination of UbXN1

Science China(Life Sciences) 2024年第6期67卷 1199-1211页

作者： Hao Wang Wenwen Chen Yanting Wang Yuzhen Gao Zizhen Zhang Shuyi Mi Liangjing Wang Meng Xue Department of Gastroenterology The Second Affiliated Hospital of Zhejiang University School of MedicineHangzhou 310009China Institution of Gastroenterology Zhejiang UniversityHangzhou 310058China Department of Clinical Laboratory Sir Run Run Shaw HospitalZhejiang University School of MedicineHangzhou 310016China Department of Gastrointestinal Oncology Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing)Peking University Cancer Hospital and InstituteBeijing 100142China

Metastasis accounts for the major cause of colorectal cancer(CRC)related mortality due to the lack of effective *** this study,we integrated the single-cell RNA-seq(sc RNA-seq)and bulk RNA-seq data and identified the transcriptional coactivator SUb1 homolog(SacSaccharomyces cerevisiae)/PC4(positive cofactor 4)associated with CRC *** SUb1 expression was correlated with advanced tumor stage and poor survival in *** vivo and vitro assays showed that SUb1 depletion could inhibit the invasive and metastatic abilities of CRC ***1 activated nf-κb signaling and its transcriptional target genes CXCL1 and CXCL3 to drive CRC ***,SUb1 integrated with the E3 ubiquitin-protein ligase UbR5 and increased its protein level in CRC ***,the increased UbR5mainly mediated Lys11-linked polyubiquitination and degradation of nf-κb negative regulator UbXN1,thus to activate the nf-κb ***,our study demonstrated that SUb1 promoted CRC progression by modulating UbR5/UbXN1 and activating nf-κb signaling,providing a new therapeutic strategy for treating metastatic CRC through targeting SUb1.

关键词： colorectal cancer Metastasis SUb1 UbR5 nf-κb signaling

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Classical swine fever virus NS5A protein antagonizes innate immune response by inhibiting the nf-κb signaling

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Virologica Sinica 2023年第6期38卷 900-910页

作者： Jinfu Sun Jiaying Li Liming Li Haixiao Yu Ping Ma Yingnan Wang Jinqi Zhu Zezhong Feng Changchun Tu Key Laboratory of bioresource Research and Development of Liaoning Province College of Life and Health SciencesNortheastern UniversityShenyang110169China Changchun Veterinary Research Institute Chinese Academy of Agricultural SciencesChangchun130122China Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Disease and Zoonoses Yangzhou UniversityYangzhou225009China

The NS5A non-structural protein of classical swine fever virus(CSFV)is a multifunctional protein involved in viral genomic replication,protein translation,assembly of infectious virus particles,and regulation of cellular signaling *** report showed that NS5A inhibited nuclear factor kappa b(nf-κb)signaling induced by poly(I:C);however,the mechanism involved has not been ***,we reported that NS5A directly interacted with nf-κb essential modulator(NEMO),a regulatory subunit of the Iκb kinase(IKK)complex,to inhibit the nf-κb signaling *** investigations showed that the zinc finger domain of NEMO and the aa 126–250 segment of NS5A are essential for the interaction between NEMO and *** analysis revealed that NS5A mediated the proteasomal degradation of *** assay showed that NS5A induced the K27-linked but not the K48-linked polyubiquitination of NEMO for proteasomal *** addition,NS5A blocked the K63-linked polyubiquitination of NEMO,thus inhibiting IKK phosphorylation,Iκbαdegradation,and nf-κb *** findings revealed a novel mechanism by which CSFV inhibits host innate immunity,which might guide the drug design against CSFV in the future.

关键词： Classical swine fever virus(CSFV) NS5A nf-κb signaling NEMO Polyubiquitination Proteasomal degradation

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Protumoral TSP50 regulates macrophage activities and polarization via induction of Tnf-α production and nf-κb signaling pathway

Protumoral TSP50 regulates macrophage activities and polariz...

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第十届全国免疫学学术大会

作者： Cheng Yang Yongli bao Luguo Sun Yuxin Li National Engineering Laboratory for Druggable Gene and Protein Screening Northeast Normal University

background:TSP50(Testes-specific protease 50)was abnormally overexpressed in many kinds of cancer tissues and ithas been proved to promote cell proliferation and *** whether TSP50 can influence the function of immune cells in the host microenvironment still remains ***:To explored the potential link between TSP50 overexpressing cells and the function and polarization of ***:We established a cell line stably overexpressing TSP50 and evaluated the regulatory effects of the conditioned medium(CM)of TSP50-overexpressing CHO cell line on macrophage phagocytosis and cytokine *** clarify the underlying ***:Our results demonstrated that the expression of inflammatory cytokines IL-1β,IL-6,IL-10,Tnf-αand TGF-βin macrophages(RAW264.7,THP-1,and mouse peritoneal macrophages)were increased after the cells were exposed to the condition medium of TSP50-overexpressing *** the same time,treatment with the condition medium of TSP50-overexpressing cells also enhances the phagocytic activities of the *** results were obtained when cocultured the macrophages with TSP50-overexpressing ***,the expression of M2b phenotype marker CCL-1 macrophages was increased after treatment with the condition medium of TSP50-overexpressing cells,whereas the M1phenotype marker CCL5 was not *** clarify the effector that influences the function and polarization of macrophages,we analyzed the cytokines expression and secretion in the TSP50-overexpressing cells,the result shown that the secretion of Tnf-αand IL-1βwere increased in the cell condition medium when overexpression of TSP50,further results revealed that the phagocytosis,cytokines production and expression of CCL-1 inmacrophages were largely decreased when down regulation of Tnf-αfrom the TSP50-overexpressing ***,we found that both condition medium and Tnf-αcan activate nf-κb signaling macrophages and pretreatment with a specific nf

关键词： TSP50 Macrophages Tumor microenvironment nf-κb signaling

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Sequestosome 1/p62： a multi-domain protein with multi-faceted functions

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Frontiers in biology 2012年第3期7卷 189-201页

作者： Xiaoyan LIU Jozsef GAL Haining ZHU Department of Molecular and Cellular biochemistry College of Medicine University of Kentucky Lexington KY 40506 USA

The sequestosome 1/p62 protein has been implicated in the regulation of a multitude of cellular processes such as nf-κb signaling, NRF2-driven oxidative stress response, protein turnover through the ubiquitin-proteasome pathway and the autophagosome/lysosome pathway, apoptosis and cellular metabolism. The domain structure of p62 also reflects this functional complexity since the protein appears to be a mosaic of protein interaction domains and motifs. Deregulation of the level and function of p62 and/or p62 mutations have been linked to a number of human diseases including Paget＇s disease of the bone, obesity, liver diseases, tumorigenesis and neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer＇s disease. In this article, we review the current understanding of the involvement of p62 in cellular processes under physiologic and pathological conditions.

关键词： sequestosome 1/p62 autophagy ubiquitin-proteasome system nf-κb signaling Paget's disease of bone,amyotrophic lateral sclerosis

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The Catalytic Triad are Essential for TSP50 to Perform Its Function in Cell Proliferation

The Catalytic Triad are Essential for TSP50 to Perform Its F...

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“细胞活动生命活力”——中国细胞生物学学会全体会员代表大会暨第十二次学术大会

作者： Yu-Yin Li~(1,2),Yong-Li bao~1,Zhen-bo Song~1,Lu-Guo Sun~(1,3),Ping Wu~1,Yu Zhang~2,Cong Fan~2,Yin Wu~2,Chun-Lei Yu~(1,2), Yan-Xin Huang~1,Ying Sun~3,Li-Hua Zheng~3,Guan-Nan Wang~3,and Yu-Xin Li~(2,3) 1.National Engineering Laboratory for Druggable Gene and Protein Screening,Northeast Normal University,Changchun 130024,China 2.Research Center of Agriculture and Medicine Gene Engineering of Ministry of Education,Northeast Normal University,Changchun 130024,China 3.Institute of Genetics and Cytology,Northeast Normal University,Changchun 130024,China

Testes-specific protease 50(TSP50),a new threonine enzyme,shares similar aa sequence and enzymatic structure with many serine proteases and is proposed to be a potential ***50 is up-regulated in breast cancer epithelial cells,and ectopic expression of TSP50 in TSP50-deficient Chinese hamster ovary(CHO) cells markedly promoted cell ***,the mechanism(s) by which TSP50 exerts its growth promotion effects are not yet fully *** delineate whether the threonine protease catalytic triad of TSP50 are essential for its function in cell proliferation,we constructed and characterized three mutant TSP50s in which point mutations were introduced in the protease catalytic triad *** a series of the proliferation,colony formation and tumorigenicity assay,we showed that TSP50 T310A and TSP50 H153A can significantly depress TSP50-induced cell proliferation and tumor *** investigation revealed that TSP50 T310A and TSP50 H153A can destroy the interaction between TSP50 and nf-kb:Iκbαcomplex which is necessary for TSP50 to perform its function in cell *** together,our data highlight the importance of the catalytic triad,especially threonine, the most critical protease catalytic site,for TSP50-induced cell proliferation and tumor formation,and the catalytic site of TSP50 would be a potential therapeutic target.

关键词： Serine protease TSP50 mechanism cell proliferation nf-κb signaling tumor formation Protein domain

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Neuroprotective effects and mechanisms of DAla2GIP-GluPAL on Alzheimer’s disease in an APP/PS1 mouse model

Neuroprotective effects and mechanisms of DAla2GIP-GluPAL on...

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中国神经科学学会第十二届全国学术会议

作者： Li-YUAN Cui-Ying ZHANG Jun-ZHANG Ling-Na HAN Jun-Ting YANG Mei-Na WU Zhao-Jun WANG Wei-YANG Jin-Shun QI Department of Physiology Changzhi Medical College Department of Neurobiology Shanxi Medical University

Objective Alzheimer’s disease（AD）, the most common type of dementia, is a devastating neurodegenerative disorder that affects a large percentage of the population. At present, there is no treatment for AD. DAla2 GIP-Glu-PAL is a newly synthetic novel enzyme-resistant GIP analogue, with 5-6 h of longer half-life, but the neuroprotective roles of DAla2 GIP-Glu-PAL especially its anti-AD effects and its underlying mechanism are still not reported to date. The present study tested the neuroprotective effects of DAla2GIP-Glu-PAL that against the synaptic plasticity and cerebral damages, and explore its possible molecular mechanisms on APP/PS1 transgenic mice. Methods The nine-month-old APP/PS1 mice and wild-type（WT） mice were divided into the following four groups: WT-PbS, APP/PS1-PbS, WT-DAla2 GIP-Glu-PAL, and APP/PS1-DAla2GIP-Glu-PAL. APP/PS1 and WT mice were injected（i.p.） with PbS（0.01 M） or DAla2GIP-Glu-PAL（5 μM） at a volume of 0.2 ml once a day for 30 days. The synaptic plasticity was measured by using in vivo hippocampal field potential recording. The neuroprotective effects of DAla2GIP-Glu-PAL were assessed by immunofluorescence double-labeling staining on hippocampus morphology of APP/PS1 transgenic mice. And the cellular and molecular mechanisms of DAla2 GIP-Glu-PAL were investigated by using Wester blotting techniques. Results（1） Chronic administration of DAla2GIP-GluPAL facilitated L-LTP induction in APP/PS1 mice at 9 months of age, as well as their WT agematched littermates.（2） Chronic administration of DAla2 GIP-Glu-PAL reduce inflammatory response of astrocytes in APP/PS1 transgenic mice.（3） Wester blotting results showed close association with the inhibition of nf-κb signaling for the neuroprotection of DAla2 GIP-Glu-PAL in AD animals. Conclusion The results demonstrate that DAla2 GIP-Glu-PAL has neuroprotective properties on in AD model mouse, this finding shows that novel GIP analogues have the potential as a novel therapeutic for AD patients.

关键词： DAla2GIP-Glu-PAL APP/PS1 transgenic mouse Synaptic plasticity nf-κb signaling Alzheimer’s disease

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