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Cell Discovery

Xiuyun Sun, Jun Wang, Xia Yao, Wen Zheng, Yang Mao, Tianlong Lan, Liguo Wang, Yonghui Sun, Xinyi Zhang, Qiuye Zhao, Jianguo Zhao, Rui-Ping Xiao, Xiuqin Zhang, Guangju Ji, Yu Rao
Although conventional genetic modification approaches for protein knockdown work very successfully due to the increasing use of CRISPR/Cas9, effective techniques for achieving protein depletion in adult animals, especially in large animals such as non-human primates, are lacking. Here, we report a chemical approach based on PROTACs technology that efficiently and quickly knocks down FKBP12 (12-kDa FK506-binding) protein globally in vivo. Both intraperitoneal and oral administration led to rapid, robust, and reversible FKBP12 degradation in mice...
2019: Cell Discovery
Longsen Han, Chao Ren, Jun Zhang, Wenjie Shu, Qiang Wang
No abstract text is available yet for this article.
2019: Cell Discovery
Yafei Cai, Guangxun Zhu, Siyang Liu, Zezheng Pan, Michaela Quintero, Candace J Poole, Chunwan Lu, Huabin Zhu, Bianca Islam, Jan van Riggelen, Darren Browning, Kebin Liu, Richard Blumberg, Nagendra Singh, Honglin Li
Intestinal exocrine secretory cells, including Paneth and goblet cells, have a pivotal role in intestinal barrier function and mucosal immunity. Dysfunction of these cells may lead to the pathogenesis of human diseases such as inflammatory bowel disease (IBD). Therefore, identification and elucidation of key molecular mechanisms that regulate the development and function of these exocrine cells would be crucial for understanding of disease pathogenesis and discovery of new therapeutic targets. The Ufm1 conjugation system is a novel ubiquitin-like modification system that consists of Ufm1 (Ubiquitin modifier 1), Uba5 (Ufm1-activating enzyme, E1), Ufc1 (Ufm1-conjugating enzyme, E2) and poorly characterized Ufm1 E3 ligase(s)...
2019: Cell Discovery
Jiayu Yu, Yang Liu, Huijia Yin, Zengyi Chang
Bacteria have long been recognized to be capable of entering a phenotypically non-growing persister state, in which the cells exhibit an extended regrowth lag and a multidrug tolerance, thus posing a great challenge in treating infectious diseases. Owing to their non-inheritability, low abundance of existence, lack of metabolic activities, and high heterogeneity, properties of persisters remain poorly understood. Here, we report our accidental discovery of a subcellular structure that we term the regrowth-delay body, which is formed only in non-growing bacterial cells and sequesters multiple key proteins...
2019: Cell Discovery
Amit Shrestha, Steve Brunette, William Lloyd Stanford, Lynn Arthur Megeney
Metacaspase enzymes are critical regulatory factors that paradoxically engage apoptosis and also maintain cell viability. For example, the Saccharomyces cerevisiae metacaspase Yca1 has been shown to be important for maintaining cellular proteostasis during stress, and the loss of this enzyme results in increased retention of aggregated material within the insoluble proteome. However, the molecular mechanism(s) by which Yca1 maintains cellular proteostasis remains unknown. Here, using proteomic analysis coupled with protein interaction studies we identified a direct interplay between Yca1 and the ubiquitin-proteasome system...
2019: Cell Discovery
Pingping Wang, Wei Wei, Wei Ye, Xiaodong Li, Wenfang Zhao, Chengshuai Yang, Chaojing Li, Xing Yan, Zhihua Zhou
Synthetic biology approach has been frequently applied to produce plant rare bioactive compounds in microbial cell factories by fermentation. However, to reach an ideal manufactural efficiency, it is necessary to optimize the microbial cell factories systemically by boosting sufficient carbon flux to the precursor synthesis and tuning the expression level and efficiency of key bioparts related to the synthetic pathway. We previously developed a yeast cell factory to produce ginsenoside Rh2 from glucose. However, the ginsenoside Rh2 yield was too low for commercialization due to the low supply of the ginsenoside aglycone protopanaxadiol (PPD) and poor performance of the key UDP-glycosyltransferase (UGT) (biopart UGTPg45) in the final step of the biosynthetic pathway...
2019: Cell Discovery
Jinhuan Chen, Xiaohua Ye, Xue-Yang Zhang, Zhengdan Zhu, Xiang Zhang, Zhijian Xu, Zhanyu Ding, Gang Zou, Qingwei Liu, Liangliang Kong, Wen Jiang, Weiliang Zhu, Yao Cong, Zhong Huang
Coxsackievirus A10 (CV-A10) belongs to the Enterovirus species A and is a causative agent of hand, foot, and mouth disease. Here we present cryo-EM structures of CV-A10 mature virion and native empty particle (NEP) at 2.84 and 3.12 Å, respectively. Our CV-A10 mature virion structure reveals a density corresponding to a lipidic pocket factor of 18 carbon atoms in the hydrophobic pocket formed within viral protein 1. By structure-guided high-throughput drug screening and subsequent verification in cell-based infection-inhibition assays, we identified four compounds that inhibited CV-A10 infection in vitro...
2019: Cell Discovery
Yang Tang, Min Chen, Li Zhou, Jian Ma, Yehua Li, Hui Zhang, Zhubing Shi, Qi Xu, Xiaoman Zhang, Ziyang Gao, Yun Zhao, Yunfeng Cheng, Shi Jiao, Zhaocai Zhou
Striatin-interacting phosphatases and kinases (STRIPAKs) are evolutionarily conserved supramolecular complexes, which have been implicated in the Hippo signaling pathway. Yet the topological structure and dynamic assembly of STRIPAK complexes remain elusive. Here, we report the overall architecture and substructures of a Hippo kinase-containing STRIPAK complex. PP2Aa/c-bound STRN3 directly contacts the Hippo kinase MST2 and also controls the loading of MST2 via two "arms" in a phosphorylation-dependent manner, one arm being STRIP1 and the other SIKE1-SLMAP...
2019: Cell Discovery
Xiong Xiao, Weifeng Lai, Huangfan Xie, Yang Liu, Weijie Guo, Yifang Liu, Yu Li, Yuanjun Li, Jingliang Zhang, Wenhan Chen, Minhui Shi, Lijun Shang, Ming Yin, Chengyan Wang, Hongkui Deng
The limited number of human hematopoietic stem cells (HSCs) has restrained their widespread clinical application. Despite great efforts in recent years, the in vitro expansion of HSCs remains a challenge due to incomplete understanding of the signaling networks underlying HSC self-renewal. Here, we show that culturing human cord blood (CB) CD34+ cells with JNK-IN-8, an inhibitor of the JNK signaling pathway, can enhance the self-renewal of HSCs with a 3.88-fold increase in cell number. These cultured CD34+ cells repopulated recipient mice for 21 weeks and can form secondary engraftment that lasted for more than 21 weeks...
2019: Cell Discovery
Xiaodan Yang, Zhulong Hu, Qiang Zhang, Shanshan Fan, Yi Zhong, Dong Guo, Yali Qin, Mingzhou Chen
Typical stress granules (tSGs) are stalled translation pre-initiation complex aggregations in the cytoplasm, and their formation is a common consequence of translation initiation inhibition under stress. We previously found that 2A protease of picornaviruses blocks tSG formation and induces atypical SG formation, but the molecular mechanism by which 2A inhibits tSG formation remains unclear. Here, we found that eukaryotic translation initiation factor 4 gamma1 (eIF4GI) is critical for tSG formation by interacting with Ras-GTPase-activating protein SH3-domain-binding protein (G3BP), and this interaction is mediated by aa 182-203 of eIF4GI and the RNA-binding domain of G3BP...
2019: Cell Discovery
Yan-Xiang Ni, Nan Zhou, Wen-Qian Xue, Li Rong, Wing-Ho Yung, Rao-Zhou Lin, Richard Yi-Tsun Kao, Zhi-Gang Duan, Hai-Tao Sun, Hua-Rui Gong, Xu-Ming Tang, Meng-Fei Liu, Wen Zhang, Shuang Qi, Sookja Chung, You-Qiang Song, Jian-Dong Huang
Kif5b-driven anterograde transport and clathrin-mediated endocytosis (CME) are responsible for opposite intracellular trafficking, contributing to plasma membrane homeostasis. However, whether and how the two trafficking processes coordinate remain unclear. Here, we show that Kif5b directly interacts with clathrin heavy chain (CHC) at a region close to that for uncoating catalyst (Hsc70) and preferentially localizes on relatively large clathrin-coated vesicles (CCVs). Uncoating in vitro is decreased for CCVs from the cortex of kif5b conditional knockout (mutant) mouse and facilitated by adding Kif5b fragments containing CHC-binding site, while cell peripheral distribution of CHC or Hsc70 keeps unaffected by Kif5b depletion...
2018: Cell Discovery
Zhifang Li, Xiaoyue Duan, Xiaomeng An, Tao Feng, Pan Li, Linlin Li, Jun Liu, Panxue Wu, Dengke Pan, Xuguang Du, Sen Wu
No abstract text is available yet for this article.
2018: Cell Discovery
Nitzan Shabek, James Ruble, Claire J Waston, Kenneth C Garbutt, Thomas R Hinds, Ti Li, Ning Zheng
No abstract text is available yet for this article.
2018: Cell Discovery
Yinjun Tian, Liming Wang
No abstract text is available yet for this article.
2018: Cell Discovery
Fei Teng, Tongtong Cui, Guihai Feng, Lu Guo, Kai Xu, Qingqin Gao, Tianda Li, Jing Li, Qi Zhou, Wei Li
The prokaryotic CRISPR-Cas adaptive immune systems provide valuable resources to develop genome editing tools, such as CRISPR-Cas9 and CRISPR-Cas12a/Cpf1. Recently, CRISPR-Cas12b/C2c1, a distinct type V-B system, has been characterized as a dual-RNA-guided DNA endonuclease system. Though being active in vitro, its cleavage activity at endogenous genome remains to be explored. Furthermore, the optimal cleavage temperature of the reported Cas12b orthologs is higher than 40 °C, which is unsuitable for mammalian applications...
2018: Cell Discovery
Yiyang Xu, Zhiyuan Yang, Lucas H Horan, Pengbo Zhang, Lianxing Liu, Bryan Zimdahl, Shon Green, Jingwei Lu, Javier F Morales, David M Barrett, Stephan A Grupp, Vivien W Chan, Hong Liu, Cheng Liu
The clinical use of genetically modified T-cell therapies has led to unprecedented response rates in leukemia and lymphoma patients treated with anti-CD19 chimeric antigen receptor (CAR)-T. Despite this clinical success, FDA-approved T-cell therapies are currently limited to B-cell malignancies, and challenges remain with managing cytokine-related toxicities. We have designed a novel antibody-T-cell receptor (AbTCR) platform where we combined the Fab domain of an antibody with the γ and δ chains of the TCR as the effector domain...
2018: Cell Discovery
Marie-Therese El-Daher, Nicolas Cagnard, Marine Gil, Marie Chansel Da Cruz, Claire Leveau, Fernando Sepulveda, Mohammed Zarhrate, Frédéric Tores, Patricia Legoix, Sylvain Baulande, Jean Pierre de Villartay, Geneviève Almouzni, Jean-Pierre Quivy, Alain Fischer, Geneviève de Saint Basile
A loss-of-function mutation in tetratricopeptide repeat domain 7A (TTC7A) is a recently identified cause of human intestinal and immune disorders. However, clues to related underlying molecular dysfunctions remain elusive. It is now shown based on the study of TTC7A-deficient and wild-type cells that TTC7A is an essential nuclear protein. It binds to chromatin, preferentially at actively transcribed regions. Its depletion results in broad range of epigenomic changes at proximal and distal transcriptional regulatory elements and in altered control of the transcriptional program...
2018: Cell Discovery
Chao Wei, Xiao Han, Danwei Weng, Qiru Feng, Xiangbing Qi, Jin Li, Minmin Luo
Heroin, nicotine, cocaine, and MDMA are abused by billions of people. They are believed to target midbrain dopamine neurons and/or serotonin neurons, but their effects on the dynamic neuronal activity remain unclear in behaving states. By combining cell-type-specific fiber photometry of Ca2+ signals and intravenous drug infusion, here we show that these four drugs of abuse profoundly modulate the activity of mouse midbrain dopamine neurons and serotonin neurons with distinct potency and kinetics. Heroin strongly activates dopamine neurons, and only excites serotonin neurons at higher doses...
2018: Cell Discovery
Mengmeng Jiang, Haide Chen, Shujing Lai, Renying Wang, Yunfei Qiu, Fang Ye, Lijiang Fei, Huiyu Sun, Yang Xu, Xinyi Jiang, Ziming Zhou, Tingyue Zhang, Yanwei Li, Jin Xie, Qun Fang, Robert Peter Gale, Xiaoping Han, He Huang, Guoji Guo
Identification of effective culture conditions to maintain and possibly expand human HSPCs in vitro is an important goal. Recent advances highlight the efficacy of chemicals in maintaining and converting cell fates. We screened 186 chemicals and found that a combination of CHIR-99021, Forskolin and OAC1 (CFO) maintained human CD34-positive cells in vitro. Efficiency of the culture system was characterized using flow cytometry for CD34-positive cells, a colony-forming assay and xeno-transplants. We found that human CD34-positive cells treated with this combination had enhanced expression of human HSPC markers and increased haematopoietic re-populating ability in immune-deficient mice...
2018: Cell Discovery
Jin Huang, Chenze Li, Ying Song, Xiaohan Fan, Ling You, Lun Tan, Lei Xiao, Qing Li, Guoran Ruan, Senlin Hu, Wei Cui, Zongzhe Li, Li Ni, Chen Chen, Anthony Yiu-Ho Woo, Rui-Ping Xiao, Dao Wen Wang
We sought to investigate the association of single nucleotide polymorphisms (SNPs) of the genes involved in βAR signaling with the response of patients to βAR blockers. A total of 2403 hospitalized patients with chronic heart failure (HF) were enrolled in a multicenter observational study as the first cohort and followed up for a mean period of 20 months. Genes for β1AR, β2AR, and the major cardiac G-protein-coupled receptor kinases (GRKs) GRK2 and GRK5 were analyzed to identify SNPs, and patients were stratified according to genotypes...
2018: Cell Discovery
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