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Classical swine fever virus NS5A protein antagonizes innate immune response by inhibiting the NF-κB signaling

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 pathways.Previous report showed that NS5A inhibited nuclear factor kappa B(NF-κB)signaling induced by poly(I:C);however,the mechanism involved has not been elucidated.Here,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 pathway.Further 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 NS5A.Mechanistic analysis revealed that NS5A mediated the proteasomal degradation of NEMO.Ubiquitination assay showed that NS5A induced the K27-linked but not the K48-linked polyubiquitination of NEMO for proteasomal degradation.In addition,NS5A blocked the K63-linked polyubiquitination of NEMO,thus inhibiting IKK phosphorylation,IκBαdegradation,and NF-κB activation.These 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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USP3 deubiquitinates and stabilizes the adapter protein ASC to regulate inflammasome activation

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Cellular & Molecular Immunology 2022年第10期19卷 1141-1152页

作者： Wanxin Zhuang Lei Zhang Yi Zheng Bingyu Liu Chunhong Ma Wei Zhao Suxia Liu Feng Liu Chengjiang Gao Key Laboratory of Infection and Immunity of Shandong Province&Key Laboratory for Experimental Teratology of Ministry of Education Shandong UniversityJinanShandong250012PR China Department of Immunology School of Biomedical SciencesShandong UniversityJinanShandong250012PR China

Inflammasomes are essential components of the innate immune system and its defense against infections,whereas the dysregulation of inflammasome activation has a detrimental effect on human health.The activation of inflammasomes is subjected to tight regulation to maintain immune homeostasis,yet the underlying mechanism remains elusive.Here,we identify USP3 as a direct deubiquitinating enzyme(DUB)for ASC,the central adapter mediating the assembly and activation of most inflammasomes.USP3 removes the K48-linked ubiquitination on ASC and strengthens its stability by blocking proteasomal degradation.Additionally,USP3 promotes inflammasome activation,and this function was confirmed in mouse models of aluminum(Alum)-induced peritonitis,F.novicida infection and flagellin-induced pneumonia in vivo.Our work unveils that USP3 functions as a key regulator of ASC ubiquitination and maintains the physiological role of ASC in mediating inflammasome activation,and we propose a new mechanism by which the ubiquitination of ASC regulates inflammasome activation.

关键词： ASC inflammasome K48-linked ubiquitination proteasomal degradation USP3

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The F-box-only protein 44 regulates pregnane X receptor protein level by ubiquitination and degradation

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Acta Pharmaceutica Sinica B 2023年第11期13卷 4523-4534页

作者： Rebecca R.Florke Gee Andrew D.Huber Jing Wu Richa Bajpai Allister J.Loughran Shondra M.Pruett-Miller Taosheng Chen Department of Chemical Biology and Therapeutics St.Jude Children's Research HospitalMemphisTN 38105USA Graduate School of Biomedical Sciences St.Jude Children's Research HospitalMemphisTN 38105USA Center for Advanced Genome Engineering and Department of Cell and Molecular Biology St.Jude Children's Research HospitalMemphisTN 38105USA

Pregnane X receptor(PXR)is a ligand-activated nuclear receptor that transcriptionally upregulates drug-metabolizing enzymes[e.g.,cytochrome P4503A4(CYP3A4)]and transporters.Although the regulation of PXR target genes is well-characterized,less is known about the regulation of PXR protein level.By screening an RNAi library,we identified the F-box-only protein 44(FBXO44)as a novel E3ligase for PXR.PXR abundance increases upon knockdown of FBXO44,and,inversely,decreases upon overexpression of FBXO44.Further analysis revealed that FBXO44 interacts with PXR,leading to its ubiquitination and proteasomal degradation,and we determined that the F-box associated domain of FBXO44 and the ligand binding domain of PXR are required for the functional interaction.In summary,FBXO44 regulates PXR protein abundance,which has downstream consequences for CYP3A4 levels and drug-drug interactions.The results of this study provide new insight into the molecular mechanisms that regulate PXR protein level and activity and suggest the importance of considering how modulating E3ubiquitin ligase activities will affect PXR-mediated drug metabolism.

关键词： PXR FBXO44 Ubiquitination proteasomal degradation CYP3A4 Drug-drug interactions E3 ligase Nuclear receptor

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Knockdown of ZBTB7A inhibits cell proliferation of breast cancer through regulating the ubiquitination of estrogen receptor alpha

Knockdown of ZBTB7A inhibits cell proliferation of breast ca...

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2021第26届广东省药师周大会

作者： Xiao Xiao Yingying Shen Liyang Yin Jun He Xiaoyu Ni Gang Luo Xiguang Chen Wenbo Zhu Jing Zhong Jianghua Liu Xiuda Peng Xuyu Zu Institute of Clinical Medicine The First Affiliated Hospital of University of South China Department of Spine Surgery The Affiliated Nanhua Hospital of University of South China

Aims: ZBTB7A, a transcriptional repressor, accelerates the breast cancer progression. Over 70% of breast cancer samples are identified as ER-α positive. Due to the function of ZBTB7A in ER-α positive breast cancer incompletely known, we aimed to determine the role of ZBTB7A in ER-α positive cancer and explore the underlying mechanisms. Main methods: In this study, the correlation between ZBTB7A and ER-α was confirmed by tissue microarray-based and TCGA database. Then, we explore if ZBTB7A maintains ER-α’s level via targeting ER-α’s expression or degradation. Finally, we examined the effect of ZBTB7A on the proliferation of breast cancer cells. Key findings: We further confirmed that ZBTB7A shows a significant positive correlation with ER-α in clinical breast cancer samples by tissue microarray-based analysis. Mechanically, we identified that the inhibition of ZBTB7A could upregulate E3 ligase TRIM25 leading to enhancement of ER-α ubiquitination and proteasomal degradation, which could partly explain the correlation between ZBTB7A and ER-α. Besides, we uncovered that ZBTB7A could also transcriptionally increase the expression of ER-α via indirectly binding to the region +146 to +461 bp downstream of the transcription start site of ESR1(ERpro315) in breast cancer cells. Furthermore, ZBTB7A is found to stimulate the expression of ER-α’s downstream genes, and promote the growth of estrogen receptor alpha(ER-α)-positive breast cancer cells. Significance: Our data revealed the novel mechanisms through which ZBTB7A manipulates ER-α level and might provide a new avenue for endocrine therapy in breast cancer.

关键词： ZBTB7A estrogen receptor alpha proteasomal degradation cell proliferation

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