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Xin Li, Adeline Gadzinsky, Liying Gong, Haijun Tong, Virginie Calderon, Yue Li, Daisuke Kitamura, Ulf Klein, Wallace Y Langdon, Fajian Hou, Yong-Rui Zou, Hua Gu
Selective expansion of high-affinity antigen-specific B cells in germinal centers (GCs) is a key event in antibody affinity maturation. GC B cells with improved affinity can either continue affinity-driven selection or exit the GC to differentiate into plasma cells (PCs) or memory B cells. Here we found that deleting E3 ubiquitin ligases Cbl and Cbl-b (Cbls) in GC B cells resulted in the early exit of high-affinity antigen-specific B cells from the GC reaction and thus impaired clonal expansion. Cbls were highly expressed in GC light zone (LZ) B cells, where they promoted the ubiquitination and degradation of Irf4, a transcription factor facilitating PC fate choice...
March 20, 2018: Immunity
Nesibe Peker, Vinay Donipadi, Mridula Sharma, Craig McFarlane, Ravi Kambadur
Parkinson's Disease is a neurodegenerative disease characterized by tremors, muscle stiffness and muscle weakness. Molecular genetic analysis confirmed that mutations in PARKIN and PINK1 genes, which play major roles in mitochondrial quality control and mitophagy, are frequently associated with Parkinson's Disease. PARKIN is an E3 ubiquitin ligase that translocates to mitochondria during loss of mitochondrial membrane potential to increase mitophagy. Although muscle dysfunction is noted in Parkinson's Disease, little is known about the involvement of PARKIN in the muscle phenotype of Parkinson's Disease...
March 21, 2018: American Journal of Physiology. Cell Physiology
Delphine Masschaele, Joris Wauman, Giel Vandemoortele, Delphine De Sutter, Leentje De Ceuninck, Sven Eyckerman, Jan Tavernier
Ring finger protein 41 (RNF41) is an E3 ubiquitin ligase involved in the ubiquitination and degradation of many proteins including ErbB3 receptors, BRUCE and parkin. Next to this, RNF41 regulates the intracellular trafficking of certain JAK2-associated cytokine receptors by ubiquitinating and suppressing USP8 which in turn destabilizes the ESCRT-0 complex. To further elucidate the function of RNF41 we used different orthogonal approaches to reveal the RNF41 protein complex: Affinity Purification-Mass Spectrometry, BioID and Virotrap...
March 21, 2018: Journal of Proteome Research
Og-Geum Woo, Soon-Hee Kim, Seok Keun Cho, Sang-Hoon Kim, Han Nim Lee, Taijoon Chung, Seong Wook Yang, Jae-Hoon Lee
BPH1 acts as a substrate receptor of CRL3 complex and negatively regulates ABA-mediated cellular responses. The study on its function provides information that helps further understand the relationship between ABA signaling and UPS. Abscisic acid (ABA) plays a crucial role in a variety of cellular processes, including seed dormancy, inhibition of seedling growth, and drought resistance in plants. Cullin3-RING E3 ligase (CRL3) complex is a type of multi-subunit E3 ligase, and BTB/POZ protein, a component of CRL3 complex, functions as a receptor to determine a specific substrate...
March 21, 2018: Plant Molecular Biology
Honghong Zhou, Yongshuo Liu, Rui Zhu, Fang Ding, Xiufeng Cao, Dongxin Lin, Zhihua Liu
Snail is a key regulator of epithelial-mesenchymal transition (EMT) and plays an important role in tumor progression and metastasis. Snail is rapidly degraded in the cells and its protein level is critically controlled. Although several E3 ligases regulating Snail degradation have been defined, the deubiquitinases (DUBs) responsible for Snail deubiquitination are less studied. We identified ovarian tumor domain-containing ubiquitin aldehyde binding protein 1 (OTUB1) as a DUB that stabilizes Snail through preventing its ubiquitination and proteasomal degradation...
March 21, 2018: Oncogene
Yuyong Tan, Deliang Liu, Jian Gong, Jia Liu, Jirong Huo
F-box only protein 31 (FBXO31), initially identified in 2005, is a novel subunit of the S-phase kinase associated protein 1-Cullin 1-F-box ubiquitin ligase. As with other F-box proteins, FBXO31 may interact with several proteins to promote their ubquitination and subsequent degradation in an F-box-dependent manner. It has been revealed that FBXO31 serves a crucial role in DNA damage response and tumorigenesis. However, the expression and function of FBXO31 varies in different types of human cancer. To the best of our knowledge, the present review is the first to summarize the role of FBXO31 in different types of human cancer and determine its underlying mechanisms, thereby paving the road for the design of FBXO31-targeted anticancer therapies...
April 2018: Oncology Letters
Xia Hou, Hongguang Wei, Carthic Rajagopalan, Hong Jiang, Qingtian Wu, Khalequz Zaman, Youming Xie, Fei Sun
Endoplasmic reticulum (ER)-associated protein degradation (ERAD) is an important quality control mechanism that eliminates misfolded proteins from the ER. The Derlin-1/VCP/VIMP protein complex plays an essential role in ERAD. Although the roles of Derlin-1 and VCP are relatively clear, the functional activity of VIMP in ERAD remains to be understood. Here we investigate the role of VIMP in the degradation of CFTRΔF508, a cystic fibrosis transmembrane conductance regulator (CFTR) mutant known to be a substrate of ERAD...
March 19, 2018: Scientific Reports
Lina Wang, Wenli Feng, Xiao Yang, Feifei Yang, Rong Wang, Qian Ren, Xiaofan Zhu, Guoguang Zheng
The ubiquitin-proteasome system (UPS) participates in both physiological and pathological processes through the posttranslational regulation of intracellular signal transduction pathways. F-box and WD-40 domain protein 11 (Fbxw11) is a component of the SCF (Skp1-Cul1-F-box) E3 ubiquitin ligase complex. Fbxw11 regulates various signal transduction pathways, and it may have pathological roles in tumorigenesis. However, the role of Fbxw11 in the development of leukemia and the underlying mechanisms remain largely unknown...
March 19, 2018: Cell Death & Disease
Yingying Zhang, Xulei Zheng, Hao Tan, Yilu Lu, Dachang Tao, Yunqiang Liu, Yongxin Ma
HDAC3 is involved in deacetylation of histone and non-histone proteins, having a key role in the regulation of gene transcription and also in the process of tumorgenesis. However, how HDAC3 is regulated in cancer remains largely unclear. Here, we showed that PIWIL2 can interact with HDAC3, leading to stabilization of HDAC3 from ubiquitin-mediated degradation by competitive association with E3 ubiquitin ligase Siah2. Furthermore, we found that expression of PIWIL2 enhanced HDAC3 activity via CK2α. PIWIL2 facilitated the interaction between HDAC3 and CK2α, thus exhibiting a promotion on the HDAC3 phosphorylation by CK2α...
March 19, 2018: Cell Death & Disease
Junli Liu, Xinfang Huang, Shumeng Hao, Yan Wang, Manman Liu, Jing Xu, Xingli Zhang, Tao Yu, Shucheng Gan, Dongfang Dai, Xuan Luo, Qingyan Lu, Chaoming Mao, Yanyun Zhang, Nan Shen, Bin Li, Mingzhu Huang, Xiaodong Zhu, Jin Jin, Xuhong Cheng, Shao-Cong Sun, Yichuan Xiao
Systemic lupus erythematosus (SLE) is characterized by uncontrolled secretion of autoantibodies by plasma cells. Although the functional importance of plasma cells and autoantibodies in SLE has been well established, the underlying molecular mechanisms of controlling autoantibody production remain poorly understood. Here we show that Peli1 has a B cell-intrinsic function to protect against lupus-like autoimmunity in mice. Peli1 deficiency in B cells induces autoantibody production via noncanonical NF-κB signaling...
March 19, 2018: Nature Communications
Julián Esteban Sáez, Cristian Arredondo, Carlos Rivera, María Estela Andrés
CoREST family of transcriptional corepressors regulates gene expression and cell fate determination during development. CoREST corepressors recruit with different affinity the histone demethylase LSD1 (KDM1A) and the deacetylases HDAC1/2 to repress with variable strength the expression of target genes. CoREST protein levels are differentially regulated during cell fate decisions and in mature tissues. However, regulatory mechanisms of CoREST corepressors at the protein level have not been studied. Here, we report that CoREST (CoREST1, RCOR1) and its homologs CoREST2 (RCOR2) and CoREST3 (RCOR3) interact with PIASγ, a SUMO-E3 ligase...
March 19, 2018: Biochemical Journal
Chao Nie, Huimin Wang, Rui Wang, David Ginsburg, Xiao-Wei Chen
The flow of cargo vesicles along the secretory pathway requires concerted action among various regulators. The COPII complex, assembled by the activated SAR1 GTPases on the surface of the endoplasmic reticulum, orchestrates protein interactions to package cargos and generate transport vesicles en route to the Golgi. The dynamic nature of COPII, however, hinders analysis with conventional biochemical assays. Here we apply proximity-dependent biotinylation labeling to capture the dynamics of COPII transport in cells...
March 19, 2018: Proceedings of the National Academy of Sciences of the United States of America
Margherita Sosio, Eleonora Gaspari, Marianna Iorio, Silvia Pessina, Marnix H Medema, Alice Bernasconi, Matteo Simone, Sonia I Maffioli, Richard H Ebright, Stefano Donadio
Pseudouridimycin (PUM) is a selective nucleoside-analog inhibitor of bacterial RNA polymerase with activity against Gram-positive and Gram-negative bacteria. PUM, produced by Streptomyces sp. ID38640, consists of a formamidinylated, N-hydroxylated Gly-Gln dipeptide conjugated to 5'-aminopseudouridine. We report the characterization of the PUM gene cluster. Bioinformatic analysis and mutational knockouts of pum genes with analysis of accumulated intermediates, define the PUM biosynthetic pathway. The work provides the first biosynthetic pathway of a C-nucleoside antibiotic and reveals three unexpected features: production of free pseudouridine by the dedicated pseudouridine synthase, PumJ; nucleoside activation by specialized oxidoreductases and aminotransferases; and peptide-bond formation by amide ligases...
February 26, 2018: Cell Chemical Biology
Huichen Li, Ye Liang, Xiaofeng Lai, Weidong Wang, Jiang Zhang, Suning Chen
Fbw7 is a type of E3 ubiquitin ligase that targets various proteins for degradation and has been found to have a high expression level in progenitor cells. Deletion of Fbw7 in the intestine results in the accumulation of progenitor cells. Moreover, Fbw7 loss increases the susceptibility of colorectal cancer. However, the involvement of Fbw7 in the progress and development of inflammatory bowel disease (IBD) is still controversial. To identify the function of Fbw7 on dextran sodium sulfate (DSS)-induced colonic inflammation, we generated Fbw7ΔG mice, lacking Fbw7 specifically in intestinal epithelium...
March 16, 2018: Biochemical and Biophysical Research Communications
Hironao Nakayama, Tomohisa Sakaue, Masashi Maekawa, Ayako Fujisaki, Shigeki Higashiyama
A disintegrin and metalloproteinase (ADAM) family are crucial enzymes for ectodomain shedding of multiple substrates and are involved in diverse biologic and pathologic processes. However, the molecular mechanism underlying substrate selectivity of ADAMs is poorly understood. In this study, we observed that disruption of actin polymerization by pharmacological inhibitors, latrunculin A (LatA) and cytochalasin D (CyD), induced ectodomain shedding of epidermal growth factor (EGF) family ligands. Induced shedding activity by LatA or CyD was suppressed by a metalloprotease inhibitor KB-R7785, indicating that ADAMs-mediated shedding is tightly controlled by actin cytoskeleton...
March 14, 2018: Biochemical and Biophysical Research Communications
Chris Chin Wah Chen, Avigail T Erlich, David A Hood
BACKGROUND: Parkin is a ubiquitin ligase that is involved in the selective removal of dysfunctional mitochondria. This process is termed mitophagy and can assist in mitochondrial quality control. Endurance training can produce adaptations in skeletal muscle toward a more oxidative phenotype, an outcome of enhanced mitochondrial biogenesis. It remains unknown whether Parkin-mediated mitophagy is involved in training-induced increases in mitochondrial content and function. Our purpose was to determine a role for Parkin in maintaining mitochondrial turnover in muscle, and its requirement in mediating mitochondrial biogenesis following endurance exercise training...
March 17, 2018: Skeletal Muscle
Cheng-Dong Ji, Yan-Xia Wang, Dong-Fang Xiang, Qiang Liu, Zhi-Hua Zhou, Feng Qian, Lang Yang, Yong Ren, Wei Cui, Sen-Lin Xu, Xi-Long Zhao, Xia Zhang, Yan Wang, Peng Zhang, Ji-Ming Wang, You-Hong Cui, Xiu-Wu Bian
Potassium ion channels are emerging as pro-malignant factors involved in cancer progression. In this study, we found that invading human gastric cancer (GC) cells express high level of inwardly rectifying potassium channel 2.1 (Kir2.1). Silencing Kir2.1 markedly reduced the invasive and metastatic capabilities as well as the epithelial-mesenchymal transition (EMT) of GC cells. The pro-malignant nature of Kir2.1 in GC cells was independent of potassium permeation but relied on its interaction with serine/threonine-protein kinase 38 (Stk38) to inhibit ubiquitination and degradation of mitogen-activated protein kinase kinase kinase 2 (MEKK2)...
March 16, 2018: Cancer Research
Hyeyoon Lee, Seong-Moon Cheong, Wonhee Han, Youngmu Koo, Saet-Byeol Jo, Gun-Sik Cho, Jae-Seong Yang, Sanguk Kim, Jin-Kwan Han
Dishevelled (Dvl/Dsh) is a key scaffold protein that propagates Wnt signaling essential for embryogenesis and homeostasis. However, whether antagonism of Wnt signaling necessary for vertebrate head formation can be achieved through regulation of Dsh protein stability is unclear. Here we show that membrane-associated RING-CH2 (March2), a RING-type E3 ubiquitin ligase, antagonizes Wnt signaling by regulating the turnover of Dsh protein via ubiquitin-mediated lysosomal degradation in prospective head region of Xenopus We further found that March2 acquires regional and functional specificities for head formation from the Dsh-interacting protein Dapper1 (Dpr1)...
March 16, 2018: Development
Tales Rocha de Moura, Sina Mozaffari-Jovin, Csaba Zoltán Kibédi Szabó, Jana Schmitzová, Olexandr Dybkov, Constantin Cretu, Michael Kachala, Dmitri Svergun, Henning Urlaub, Reinhard Lührmann, Vladimir Pena
Human nineteen complex (NTC) acts as a multimeric E3 ubiquitin ligase in DNA repair and splicing. The transfer of ubiquitin is mediated by Prp19-a homotetrameric component of NTC whose elongated coiled coils serve as an assembly axis for two other proteins called SPF27 and CDC5L. We find that Prp19 is inactive on its own and have elucidated the structural basis of its autoinhibition by crystallography and mutational analysis. Formation of the NTC core by stepwise assembly of SPF27, CDC5L, and PLRG1 onto the Prp19 tetramer enables ubiquitin ligation...
March 15, 2018: Molecular Cell
Guillaume Dubeaux, Julie Neveu, Enric Zelazny, Grégory Vert
Plant roots forage the soil for iron, the concentration of which can be dramatically lower than those needed for growth. Soil iron uptake uses the broad metal spectrum IRT1 transporter that also transports zinc, manganese, cobalt, and cadmium. Sophisticated iron-dependent transcriptional regulatory mechanisms allow plants to tightly control the abundance of IRT1, ensuring optimal absorption of iron. Here, we uncover that IRT1 acts as a transporter and receptor (transceptor), directly sensing excess of its non-iron metal substrates in the cytoplasm, to regulate its own degradation...
March 15, 2018: Molecular Cell
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