Latest Articles

Mitochondrion-processed TERC regulates senescence without affecting telomerase activities
Qian Zheng, Peipei Liu, Ge Gao, Jiapei Yuan, Pengfeng Wang, Jinliang Huang, Leiming Xie, Xinping Lu, Fan Di, Tanjun Tong, Jun Chen, Zhi Lu, Jisong Guan, Geng Wang
 doi: 10.1007/s13238-019-0612-5
Mitochondrial dysfunctions play major roles in ageing. How mitochondrial stresses invoke downstream responses and how specificity of the signaling is achieved, however, remains unclear. We have previously discovered that the RNA component of Telomerase TERC is imported into mitochondria, processed to a shorter form TERC-53, and then exported back to the cytosol. Cytosolic TERC-53 levels respond to mitochondrial functions, but have no direct effect on these functions, suggesting that cytosolic TERC-53 functions downstream of mitochondria as a signal of mitochondrial functions. Here, we show that cytosolic TERC-53 plays a regulatory role on cellular senescence and is involved in cognition decline in 10 months old mice, independent of its telomerase function. Manipulation of cytosolic TERC-53 levels affects cellular senescence and cognition decline in 10 months old mouse hippocampi without affecting telomerase activity, and most importantly, affects cellular senescence in terc-/- cells. These findings uncover a senescence-related regulatory pathway with a non-coding RNA as the signal in mammals.
PKM2 coordinates glycolysis with mitochondrial fusion and oxidative phosphorylation
Tong Li, Jinbo Han, Liangjie Jia, Xiao Hu, Liqun Chen, Yiguo Wang
 doi: 10.1007/s13238-019-0618-z
A change in the metabolic flux of glucose from mitochondrial oxidative phosphorylation (OXPHOS) to aerobic glycolysis is regarded as one hallmark of cancer. However, the mechanisms underlying the metabolic switch between aerobic glycolysis and OXPHOS are unclear. Here we show that the M2 isoform of pyruvate kinase (PKM2), one of the rate-limiting enzymes in glycolysis, interacts with mitofusin 2 (MFN2), a key regulator of mitochondrial fusion, to promote mitochondrial fusion and OXPHOS, and attenuate glycolysis. mTOR increases the PKM2:MFN2 interaction by phosphorylating MFN2 and thereby modulates the effect of PKM2: MFN2 on glycolysis, mitochondrial fusion and OXPHOS. Thus, an mTOR-MFN2-PKM2 signaling axis couples glycolysis and OXPHOS to modulate cancer cell growth.
Correction to: A binding-block ion selective mechanism revealed by a Na/K selective channel
Jie Yu, Bing Zhang, Yixiao Zhang, Cong-qiao Xu, Wei Zhuo, Jingpeng Ge, Jun Li, Ning Gao, Yang Li, Maojun Yang
 doi: 10.1007/s13238-019-0619-y
In vitro transcribed sgRNA causes cell death by inducing interferon release
Wei Mu, Na Tang, Chen Cheng, Wen Sun, Xiaofei Wei, Haoyi Wang
 doi: 10.1007/s13238-018-0605-9
RETRACTED ARTICLE: DDB1 and Cul4 are necessary for gene silencing and heterochromatin formation at pericentromeric regions in Neurospora
Yingqiong Cao, Jicheng Wei, Silu Yang, Jinquan Sun, Hui Xu, Ying Wang, Yuanbiao Zhao, Qun He
 doi: 10.1007/s13238-014-0067-7
A miRNA-HERC4 pathway promotes breast tumorigenesis by inactivating tumor suppressor LATS1
Youqin Xu, Kaiyuan Ji, Meng Wu, Bingtao Hao, Kai-tai Yao, Yang Xu
 doi: 10.1007/s13238-019-0607-2
The E3 ligase HERC4 is overexpressed in human breast cancer and its expression levels correlated with the prognosis of breast cancer patients. However, the roles of HERC4 in mammary tumorigenesis remain unclear. Here we demonstrate that the knockdown of HERC4 in human breast cancer cells dramatically suppressed their proliferation, survival, migration, and tumor growth in vivo, while the overexpression of HERC4 promoted their aggressive tumorigenic activities. HERC4 is a new E3 ligase for the tumor suppressor LATS1 and destabilizes LATS1 by promoting the ubiquitination of LATS1. miRNA-136-5p and miRNA-1285-5p, expression of which is decreased in human breast cancers and is inversely correlated with the prognosis of breast cancer patients, are directly involved in suppressing the expression of HERC4. In summary, we discover a miRNA-HERC4- LATS1 pathway that plays important roles in the pathogenesis of breast cancer and represents new therapeutic targets for human breast cancer.
PCGF6 regulates stem cell pluripotency as a transcription activator via super-enhancer dependent chromatin interactions
Xiaona Huang, Chao Wei, Fenjie Li, Lumeng Jia, Pengguihang Zeng, Jiahe Li, Jin Tan, Tuanfeng Sun, Shaoshuai Jiang, Jia Wang, Xiuxiao Tang, Qingquan Zhao, Bin Liu, Limin Rong, Cheng Li, Junjun Ding
 doi: 10.1007/s13238-019-0629-9
Polycomb group (PcG) ring finger protein 6 (PCGF6), though known as a member of the transcription-repressing complexes, PcG, also has activation function in regulating pluripotency gene expression. However, the mechanism underlying the activation function of PCGF6 is poorly understood. Here, we found that PCGF6 co-localizes to gene activation regions along with pluripotency factors such as OCT4. In addition, PCGF6 was recruited to a subset of the super-enhancer (SE) regions upstream of cell cycle-associated genes by OCT4, and increased their expression. By combining with promoter capture Hi-C data, we found that PCGF6 activates cell cycle genes by regulating SE-promoter interactions via 3D chromatin. Our findings highlight a novel mechanism of PcG protein in regulating pluripotency, and provide a research basis for the therapeutic application of pluripotent stem cells.
Neuroendocrine characteristics of induced pluripotent stem cells from polycystic ovary syndrome women
Zheying Min, Yue Zhao, Jing Hang, Yun Ren, Tao Tan, Yong Fan, Yang Yu
 doi: 10.1007/s13238-018-0600-1
Correction to: Prof. Huan-Yong Chen: a leading botanist and taxonomist, one of the pioneers and founders of modern plant taxonomy in China
Rui-Lan Huang
 doi: 10.1007/s13238-018-0569-9
Crystal structure of Lamellipodin implicates diverse functions in actin polymerization and Ras signaling
Yu-Chung Chang, Hao Zhang, Mark L. Brennan, Jinhua Wu
 doi: 10.1007/s13238-012-2082-x
The adapter protein Lamellipodin (Lpd) plays an important role in cell migration. In particular, Lpd mediates lamellipodia formation by regulating actin dynamics via interacting with Ena/VASP proteins. Its RA-PH tandem domain configuration suggests that like its paralog RIAM, Lpd may also mediate particular Ras GTPase signaling. We determined the crystal structures of the Lpd RA-PH domains alone and with an N-terminal coiled-coil region (cc-RA-PH). These structures reveal that apart from the anticipated coiled-coil interaction, Lpd may also oligomerize through a second intermolecular contact site. We then validated both oligomerization interfaces in solution by mutagenesis. A fluorescence-polarization study demonstrated that Lpd binds phosphoinositol with low affinity. Based on our crystallographic and biochemical data, we propose that Lpd and RIAM serve diverse functions:Lpd plays a predominant role in regulating actin polymerization, and its function in mediating Ras GTPase signaling is largely suppressed compared to RIAM.
Unbiased transcriptomic analyses reveal distinct effects of immune deficiency in CNS function with and without injury
Dandan Luo, Weihong Ge, Xiao Hu, Chen Li, Chia-Ming Lee, Liqiang Zhou, Zhourui Wu, Juehua Yu, Sheng Lin, Jing Yu, Wei Xu, Lei Chen, Chong Zhang, Kun Jiang, Xingfei Zhu, Haotian Li, Xinpei Gao, Yanan Geng, Bo Jing, Zhen Wang, Changhong Zheng, Rongrong Zhu, Qiao Yan, Quan Lin, Keqiang Ye, Yi E. Sun, Liming Cheng
 doi: 10.1007/s13238-018-0559-y
The mammalian central nervous system (CNS) is considered an immune privileged system as it is separated from the periphery by the blood brain barrier (BBB). Yet, immune functions have been postulated to heavily influence the functional state of the CNS, especially after injury or during neurodegeneration. There is controversy regarding whether adaptive immune responses are beneficial or detrimental to CNS injury repair. In this study, we utilized immunocompromised SCID mice and subjected them to spinal cord injury (SCI). We analyzed motor function, electrophysiology, histochemistry, and performed unbiased RNA-sequencing. SCID mice displayed improved CNS functional recovery compared to WT mice after SCI. Weighted gene-coexpression network analysis (WGCNA) of spinal cord transcriptomes revealed that SCID mice had reduced expression of immune function-related genes and heightened expression of neural transmission-related genes after SCI, which was confirmed by immunohistochemical analysis and was consistent with better functional recovery. Transcriptomic analyses also indicated heightened expression of neurotransmission-related genes before injury in SCID mice, suggesting that a steady state of immune-deficiency potentially led to CNS hyper-connectivity. Consequently, SCID mice without injury demonstrated worse performance in Morris water maze test. Taken together, not only reduced inflammation after injury but also dampened steady-state immune function without injury heightened the neurotransmission program, resulting in better or worse behavioral outcomes respectively. This study revealed the intricate relationship between immune and nervous systems, raising the possibility for therapeutic manipulation of neural function via immune modulation.
Weisun Tao: a pioneer of biochemistry in China
Tianwei He
 doi: 10.1007/s13238-017-0383-9
Cells derived from iPSC can be immunogenic-Yes or No?
Jiani Cao, Xiaoyan Li, Xiao Lu, Chao Zhang, Honghao Yu, Tongbiao Zhao
 doi: 10.1007/s13238-013-3909-9
The induced pluripotent stem cells (iPSCs), derived by ectopic expression of reprogramming factors in somatic cells, can potentially provide unlimited autologous cells for regenerative medicine. In theory, the autologous cells derived from patient iPSCs should be immune tolerant by the host without any immune rejections. However, our recent studies have found that even syngeneic iPSC-derived cells can be immunogenic in syngeneic hosts by using a teratoma transplantation model (Zhao et al., 2011). Recently two research groups differentiated the iPSCs into different germ layers or cells, transplanted those cells to the syngeneic hosts, and evaluated the immunogenicity of those cells. Both of the two studies support our conclusions that some certain but not all tissues derived from iPSCs can be immunogenic, although they claimed either "negligible" or "lack of" immunogenicity in iPSC derivatives (Araki et al., 2013; Guha et al., 2013). To test the immunogenicity of clinically valuable cells differentiated from human iPSCs are emergently required for translation of iPSC technology to clinics.
Structural insights into the species preference of the influenza B virus NS1 protein in ISG15 binding
Yinan Jiang, Xinquan Wang
 doi: 10.1007/s13238-018-0598-4
Mutations in foregut SOX2+ cells induce efficient proliferation via CXCR2 pathway
Tomoaki Hishida, Eric Vazquez-Ferrer, Yuriko Hishida-Nozaki, Ignacio Sancho-Martinez, Yuta Takahashi, Fumiyuki Hatanaka, Jun Wu, Alejandro Ocampo, Pradeep Reddy, Min-Zu Wu, Laurie Gerken, Reuben J. Shaw, Concepcion Rodriguez Esteban, Christopher Benner, Hiroshi Nakagawa, Pedro Guillen Garcia, Estrella Nuñez Delicado, Antoni Castells, Josep M. Campistol, Guang-Hui Liu, Juan Carlos Izpisua Belmonte
 doi: 10.1007/s13238-019-0630-3
Identification of the precise molecular pathways involved in oncogene-induced transformation may help us gain a better understanding of tumor initiation and promotion. Here, we demonstrate that SOX2+ foregut epithelial cells are prone to oncogenic transformation upon mutagenic insults, such as KrasG12D and p53 deletion. GFP-based lineage-tracing experiments indicate that SOX2+ cells are the cells-of-origin of esophagus and stomach hyperplasia. Our observations indicate distinct roles for oncogenic KRAS mutation and P53 deletion. p53 homozygous deletion is required for the acquisition of an invasive potential, and KrasG12D expression, but not p53 deletion, suffices for tumor formation. Global gene expression analysis reveals secreting factors upregulated in the hyperplasia induced by oncogenic KRAS and highlights a crucial role for the CXCR2 pathway in driving hyperplasia. Collectively, the array of genetic models presented here demonstrate that stratified epithelial cells are susceptible to oncogenic insults, which may lead to a better understanding of tumor initiation and aid in the design of new cancer therapeutics.
Richang Cao: pioneer advocate of dialectical materialism applied to psychological research
Baoyuan Zhang
 doi: 10.1007/s13238-019-0615-2
In vivo tunable CRISPR mediates efficient somatic mutagenesis to generate tumor models
Xiaomeng An, Linlin Li, Sen Wu
 doi: 10.1007/s13238-018-0579-7
In memory of Prof. C. C. Li
Zhi Xia, Juan Tian, Xiaoling Wang, Huanming Yang
 doi: 10.1007/s13238-018-0583-y
Propofol reduces synaptic strength by inhibiting sodium and calcium channels at nerve terminals
Qing-Zhuo Liu, Mei Hao, Zi-Yang Zhou, Jian-Long Ge, Yi-Chen Wu, Ling-Ling Zhao, Xiang Wu, Yi Feng, Hong Gao, Shun Li, Lei Xue
 doi: 10.1007/s13238-019-0624-1
Zing-Yang Kuo and behavior epigenesis based on animal experiments
Yanyan Qian, Wei Chen, Benyu Guo
 doi: 10.1007/s13238-018-0516-9
Basic and translational aging research in China: present and future
Xiaojuan He, Moshi Song, Jing Qu, Yansu Guo, Heqi Cao, Ruijuan Sun, Guang-Hui Liu, Yong Shen, Major Program Expert Group
 doi: 10.1007/s13238-019-0617-0
The percentage of elderly people in the world is increasing at an unprecedented pace; so it is in China, which has the world’s largest population and a high ratio of the seniors (aged 60 and above) to working-age adults. The growing elderly population is presenting a major social challenge. Accordingly, it is not only imperative as a national strategic demand but also promises great scientific values to understand the biological process of aging, explore the mystery of healthy aging, delay the aging process, and treat the age-related diseases. This Perspective summarizes past and present advances of the basic and translational aging research in China and offers perspectives on future endeavors in this area.
Targeting tissue-specific metabolic signaling pathways in aging: the promise and limitations
Fang Hu, Feng Liu
 doi: 10.1007/s13238-013-3077-y
It has been well established that most of the age-related diseases such as insulin resistance, type 2 diabetes, hypertension, cardiovascular disease, osteoporosis, and atherosclerosis are all closely related to metabolic dysfunction. On the other hand, interventions on metabolism such as calorie restriction or genetic manipulations of key metabolic signaling pathways such as the insulin and mTOR signaling pathways slow down the aging process and improve healthy aging. These findings raise an important question as to whether improving energy homeostasis by targeting certain metabolic signaling pathways in specific tissues could be an effective anti-aging strategy. With a more comprehensive understanding of the tissuespecific roles of distinct metabolic signaling pathways controlling energy homeostasis and the cross-talks between these pathways during aging may lead to the development of more effective therapeutic interventions not only for metabolic dysfunction but also for aging.
Human germline editing: Insights to future clinical treatment of diseases
Yanni Li, Xiang Jin Kang, Jeremy Kah Sheng Pang, Boon Seng Soh, Yang Yu, Yong Fan
 doi: 10.1007/s13238-018-0594-8
Histone deacetylase 6 and cytoplasmic linker protein 170 function together to regulate the motility of pancreatic cancer cells
Dengwen Li, Xiaodong Sun, Linlin Zhang, Bing Yan, Songbo Xie, Ruming Liu, Min Liu, Jun Zhou
 doi: 10.1007/s13238-013-3098-6
Pancreatic cancer is a devastating disease with the worst prognosis among all the major human malignancies. The propensity to rapidly metastasize contributes significantly to the highly aggressive feature of pancreatic cancer. The molecular mechanisms underlying this remain elusive, and proteins involved in the control of pancreatic cancer cell motility are not fully characterized. In this study, we find that histone deacetylase 6 (HDAC6), a member of the class Ⅱ HDAC family, is highly expressed at both protein and mRNA levels in human pancreatic cancer tissues. HDAC6 does not obviously affect pancreatic cancer cell proliferation or cell cycle progression. Instead, it significantly promotes the motility of pancreatic cancer cells. Further studies reveal that HDAC6 interacts with cytoplasmic linker protein 170 (CLIP-170) and that these two proteins function together to stimulate the migration of pancreatic cancer cells. These findings provide mechanistic insight into the progression of pancreatic cancer and suggest HDAC6 as a potential target for the management of this malignancy.
Tongue coating microbiome as a potential biomarker for gastritis including precancerous cascade
Jiaxing Cui, Hongfei Cui, Mingran Yang, Shiyu Du, Junfeng Li, Yingxue Li, Liyang Liu, Xuegong Zhang, Shao Li
 doi: 10.1007/s13238-018-0596-6
The development of gastritis is associated with an increased risk of gastric cancer. Current invasive gastritis diagnostic methods are not suitable for monitoring progress. In this work based on 78 gastritis patients and 50 healthy individuals, we observed that the variation of tongue-coating microbiota was associated with the occurrence and development of gastritis. Twenty-one microbial species were identified for differentiating tongue-coating microbiomes of gastritis and healthy individuals. Pathways such as microbial metabolism in diverse environments, biosynthesis of antibiotics and bacterial chemotaxis were up-regulated in gastritis patients. The abundance of Campylobacter concisus was found associated with the gastric precancerous cascade. Furthermore, Campylobacter concisus could be detected in tongue coating and gastric fluid in a validation cohort containing 38 gastritis patients. These observations provided biological evidence of tongue diagnosis in traditional Chinese medicine, and indicated that tongue-coating microbiome could be a potential non-invasive biomarker, which might be suitable for long-term monitoring of gastritis.
Equilibria between the K+ binding and cation vacancy conformations of potassium channels
Yao He, Bo Zhang, Hao Dong, Penglin Xu, Xiaoying Cai, Ting Zhou, Mu Yu, Jun Liang, Xiao Zheng, Changlin Tian
 doi: 10.1007/s13238-019-0609-0
The effect of clinical-grade retinal pigment epithelium derived from human embryonic stem cells using different transplantation strategies
Lei Wang, Wei Wu, Qi Gu, Zengping Liu, Qiyou Li, Zhongwen Li, Jinhui Fang, Wenjing Liu, Jun Wu, Ying Zhang, Liu Wang, Haiwei Xu, Wei Li, Baoyang Hu, Qi Zhou, Zhengqin Yin, Jie Hao
 doi: 10.1007/s13238-018-0606-8
Shitsan Pai: the establishment of the first biophysics department in the world
Rui Liu
 doi: 10.1007/s13238-018-0557-0
Retraction Note to: DDB1 and Cul4 are necessary for gene silencing and heterochromatin formation at pericentromeric regions in Neurospora
Yingqiong Cao, Jicheng Wei, Silu Yang, Jinquan Sun, Hui Xu, Ying Wang, Yuanbiao Zhao, Qun He
 doi: 10.1007/s13238-014-0079-3
VHL-1 inactivation and mitochondrial antioxidants rescue C. elegans dopaminergic neurodegeneration
Song Chen, Shuo Luo, Zhe Zhang, Dengke K. Ma
 doi: 10.1007/s13238-019-0621-4
Sialylation is involved in cell fate decision during development, reprogramming and cancer progression
Fenjie Li, Junjun Ding
 doi: 10.1007/s13238-018-0597-5
Sialylation, or the covalent addition of sialic acid to the terminal end of glycoproteins, is a biologically important modification that is involved in embryonic development, neurodevelopment, reprogramming, oncogenesis and immune responses. In this review, we have given a comprehensive overview of the current literature on the involvement of sialylation in cell fate decision during development, reprogramming and cancer progression. Sialylation is essential for early embryonic development and the deletion of UDP-GlcNAc 2-epimerase, a rate-limiting enzyme in sialic acid biosynthesis, is embryonically lethal. Furthermore, the sialyltransferase ST6GAL1 is required for somatic cell reprogramming, and its downregulation is associated with decreased reprogramming efficiency. In addition, sialylation levels and patterns are altered during cancer progression, indicating the potential of sialylated molecules as cancer biomarkers. Taken together, the current evidences demonstrate that sialylation is involved in crucial cell fate decision.
Colonization process of Arabidopsis thaliana roots by a green fluorescent protein-tagged isolate of Verticillium dahliae
Pan Zhao, Yun-Long Zhao, Yun Jin, Tao Zhang, Hui-Shan Guo
 doi: 10.1007/s13238-013-3061-6
Chemical screen identifies a geroprotective role of quercetin in premature aging
Lingling Geng, Zunpeng Liu, Weiqi Zhang, Wei Li, Zeming Wu, Wei Wang, Ruotong Ren, Yao Su, Peichang Wang, Liang Sun, Zhenyu Ju, Piu Chan, Moshi Song, Jing Qu, Guang-Hui Liu
 doi: 10.1007/s13238-018-0567-y
Aging increases the risk of various diseases. The main goal of aging research is to find therapies that attenuate aging and alleviate aging-related diseases. In this study, we screened a natural product library for geroprotective compounds using Werner syndrome (WS) human mesenchymal stem cells (hMSCs), a premature aging model that we recently established. Ten candidate compounds were identified and quercetin was investigated in detail due to its leading effects. Mechanistic studies revealed that quercetin alleviated senescence via the enhancement of cell proliferation and restoration of heterochromatin architecture in WS hMSCs. RNA-sequencing analysis revealed the transcriptional commonalities and differences in the geroprotective effects by quercetin and Vitamin C. Besides WS hMSCs, quercetin also attenuated cellular senescence in Hutchinson-Gilford progeria syndrome (HGPS) and physiological-aging hMSCs. Taken together, our study identifies quercetin as a geroprotective agent against accelerated and natural aging in hMSCs, providing a potential therapeutic intervention for treating age-associated disorders.
Developing potent PROTACs tools for selective degradation of HDAC6 protein
Zixuan An, Wenxing Lv, Shang Su, Wei Wu, Yu Rao
 doi: 10.1007/s13238-018-0602-z
Jiao Shao: A forerunner of physiological psychology and comparative psychology in China
Lijun Wang, Yanyan Qian, Yanjie Su
 doi: 10.1007/s13238-018-0592-x
Tonghua Liu: A life dedicated to clinical pathology
Lin Dong, Tanping Fu, Junyi Pang, Zhiyong Liang, Wenli Duan
 doi: 10.1007/s13238-018-0601-0
IL-2 and IL-15 dependent thymic development of Foxp3-expressing regulatory T lymphocytes
Cécile Apert, Paola Romagnoli, Joost P. M. van Meerwijk
 doi: 10.1007/s13238-017-0425-3
Immunosuppressive regulatory T lymphocytes (Treg) expressing the transcription factor Foxp3 play a vital role in the maintenance of tolerance of the immunesystem to self and innocuous non-self. Most Treg that are critical for the maintenance of tolerance to self, develop as an independent T-cell lineage from common T cell precursors in the thymus. In this organ, their differentiation requires signals from the T cell receptor for antigen, from co-stimulatory molecules, as well as from cytokine-receptors. Here we focus on the cytokines implicated in thymic development of Treg, with a particular emphasis on the roles of interleukin-2 (IL-2) and IL-15. The more recently appreciated involvement of TGF-β in thymic Treg development is also briefly discussed. Finally, we discuss how cytokine-dependence of Treg development allows for temporal, quantitative, and potentially qualitative modulation of this process.
Crystal structure and function of Rbj: A constitutively GTP-bound small G protein with an extra DnaJ domain
Zhengrong Gao, Keke Xing, Chang Zhang, Jianxun Qi, Liang Wang, Shan Gao, Ren Lai
 doi: 10.1007/s13238-019-0622-3
Correction to: Gene activation in human cells using CRISPR/Cpf1-p300 and CRISPR/Cpf1-SunTag systems
Xin Zhang, Wei Wang, Lin Shan, Le Han, Shufeng Ma, Yan Zhang, Bingtao Hao, Ying Lin, Zhili Rong
 doi: 10.1007/s13238-018-0585-9
Neddylation inhibitor MLN4924 suppresses cilia formation by modulating AKT1
Hongmei Mao, Zaiming Tang, Hua Li, Bo Sun, Mingjia Tan, Shaohua Fan, Yuan Zhu, Yi Sun
 doi: 10.1007/s13238-019-0614-3
The primary cilium is a microtubule-based sensory organelle. The molecular mechanism that regulates ciliary dynamics remains elusive. Here, we report an unexpected finding that MLN4924, a small molecule inhibitor of NEDD8-activating enzyme (NAE), blocks primary ciliary formation by inhibiting synthesis/ assembly and promoting disassembly. This is mainly mediated by MLN4924-induced phosphorylation of AKT1 at Ser473 under serum-starved, ciliary-promoting conditions. Indeed, pharmaceutical inhibition (by MK2206) or genetic depletion (via siRNA) of AKT1 rescues MLN4924 effect, indicating its causal role. Interestingly, pAKT1-Ser473 activity regulates both ciliary synthesis/ assembly and disassembly in a MLN4924 dependent manner, whereas pAKT-Thr308 determines the ciliary length in MLN4924-independent but VHL-dependent manner. Finally, MLN4924 inhibits mouse hair regrowth, a process requires ciliogenesis. Collectively, our study demonstrates an unexpected role of a neddylation inhibitor in regulation of ciliogenesis via AKT1, and provides a proof-of-concept for potential utility of MLN4924 in the treatment of human diseases associated with abnormal ciliogenesis.
Correction to: Glycosylation of dentin matrix protein 1 is a novel key element for astrocyte maturation and BBB integrity
Bo Jing, Chunxue Zhang, Xianjun Liu, Liqiang Zhou, Jiping Liu, Yinan Yao, Juehua Yu, Yuteng Weng, Min Pan, Jie Liu, Zuolin Wang, Yao Sun, Yi Eve Sun
 doi: 10.1007/s13238-018-0574-z
Retraction Note: Cryptomycota: the missing link
Krishna Bolla, Elizabeth Jane Ashforth
 doi: 10.1007/s13238-012-2820-0
Current advances in haploid stem cells
Tongtong Cui, Zhikun Li, Qi Zhou, Wei Li
 doi: 10.1007/s13238-019-0625-0
Diploidy is the typical genomic mode in all mammals. Haploid stem cells are artificial cell lines experimentally derived in vitro in the form of different types of stem cells, which combine the characteristics of haploidy with a broad developmental potential and open the possibility to uncover biological mysteries at a genomic scale. To date, a multitude of haploid stem cell types from mouse, rat, monkey and humans have been derived, as more are in development. They have been applied in high-throughput genetic screens and mammalian assisted reproduction. Here, we review the generation, unique properties and broad applications of these remarkable cells.
Correction to: Developing potent PROTACs tools for selective degradation of HDAC6 protein
Zixuan An, Wenxing Lv, Shang Su, Wei Wu, Yu Rao
 doi: 10.1007/s13238-019-0613-4
Professor Yongjia Duan: a distinguished plant pathologist and agricultural educator
Fei Du, Wei-Ping Deng, Xia-Hong He, Hong Cai, You-Yong Zhu
 doi: 10.1007/s13238-019-0616-1
Professor Cuifen Huang: a great molecular geneticist and the founder of genetic engineering in China
Wei Gong, Leyi Cui, Yike Ying, Yijing Shen, Jiaqi Bao
 doi: 10.1007/s13238-019-0620-5
Screening for mutations in human cardiomyopathy- is RBM24 a new but rare disease gene?
Anna Gaertner, Andreas Brodehl, Hendrik Milting
 doi: 10.1007/s13238-018-0590-z
Rescue of premature aging defects in Cockayne syndrome stem cells by CRISPR/ Cas9-mediated gene correction
Si Wang, Zheying Min, Qianzhao Ji, Lingling Geng, Yao Su, Zunpeng Liu, Huifang Hu, Lixia Wang, Weiqi Zhang, Keiichiro Suzuiki, Yu Huang, Puyao Zhang, Tie-Shan Tang, Jing Qu, Yang Yu, Guang-Hui Liu, Jie Qiao
 doi: 10.1007/s13238-019-0623-2
Cockayne syndrome (CS) is a rare autosomal recessive inherited disorder characterized by a variety of clinical features, including increased sensitivity to sunlight, progressive neurological abnormalities, and the appearance of premature aging. However, the pathogenesis of CS remains unclear due to the limitations of current disease models. Here, we generate integration-free induced pluripotent stem cells (iPSCs) from fibroblasts from a CS patient bearing mutations in CSB/ERCC6 gene and further derive isogenic genecorrected CS-iPSCs (GC-iPSCs) using the CRISPR/Cas9 system. CS-associated phenotypic defects are recapitulated in CS-iPSC-derived mesenchymal stem cells (MSCs) and neural stem cells (NSCs), both of which display increased susceptibility to DNA damage stress. Premature aging defects in CS-MSCs are rescued by the targeted correction of mutant ERCC6. We next map the transcriptomic landscapes in CS-iPSCs and GC-iPSCs and their somatic stem cell derivatives (MSCs and NSCs) in the absence or presence of ultraviolet (UV) and replicative stresses, revealing that defects in DNA repair account for CS pathologies. Moreover, we generate autologous GC-MSCs free of pathogenic mutation under a cGMP (Current Good Manufacturing Practice)-compliant condition, which hold potential for use as improved biomaterials for future stem cell replacement therapy for CS. Collectively, our models demonstrate novel disease features and molecular mechanisms and lay a foundation for the development of novel therapeutic strategies to treat CS.
A 110-year-old wise man: Professor Libin T. Cheng, one of the founders of biochemistry and nutrition in China
He Zhang
 doi: 10.1007/s13238-017-0428-0
Professor Li-Pin. King: a famous physiologist in China
Wei Gong, Fangfang Wang, Yike Ying
 doi: 10.1007/s13238-018-0582-z
Professor Tafu Yu: an eminent agricultural scientist and outstanding educator of our nation
Shuang Zhao, Tiantian Xu, Hexiang Wang
 doi: 10.1007/s13238-017-0494-3
RNA binding protein 24 deletion disrupts global alternative splicing and causes dilated cardiomyopathy
Jing Liu, Xu Kong, Mengkai Zhang, Xiao Yang, Xiuqin Xu
 doi: 10.1007/s13238-018-0578-8
RNA splicing contributes to a broad spectrum of posttranscriptional gene regulation during normal development, as well as pathological manifestation of heart diseases. However, the functional role and regulation of splicing in heart failure remain poorly understood. RNA binding protein (RBP), a major component of the splicing machinery, is a critical factor in this process. RNA binding motif protein 24 (RBM24) is a tissue-specific RBP which is highly expressed in human and mouse heart. Previous studies demonstrated the functional role of RBM24 in the embryonic heart development. However, the role of RBM24 in postnatal heart development and heart disease has not been investigated. In this paper, using conditional RBM24 knockout mice, we demonstrated that ablation of RBM24 in postnatal heart led to rapidly progressive dilated cardiomyopathy (DCM), heart failure, and postnatal lethality. Global splicing profiling revealed that RBM24 regulated a network of genes related to cardiac function and diseases. Knockout of RBM24 resulted in misregulation of these splicing transitions which contributed to the subsequent development of cardiomyopathy. Notably, our analysis identified RBM24 as a splice factor that determined the splicing switch of a subset of genes in the sacomeric Z-disc complex, including Titin, the major disease gene of DCM and heart failure. Together, this study identifies regulation of RNA splicing by RBM24 as a potent player in remodeling of heart during postnatal development, and provides novel mechanistic insights to the pathogenesis of DCM.
Telomere-dependent and telomereindependent roles of RAP1 in regulating human stem cell homeostasis
Xing Zhang, Zunpeng Liu, Xiaoqian Liu, Si Wang, Yiyuan Zhang, Xiaojuan He, Shuhui Sun, Shuai Ma, Ng Shyh-Chang, Feng Liu, Qiang Wang, Xiaoqun Wang, Lin Liu, Weiqi Zhang, Moshi Song, Guang-Hui Liu, Jing Qu
 doi: 10.1007/s13238-019-0610-7
RAP1 is a well-known telomere-binding protein, but its functions in human stem cells have remained unclear. Here we generated RAP1-deficient human embryonic stem cells (hESCs) by using CRISPR/Cas9 technique and obtained RAP1-deficient human mesenchymal stem cells (hMSCs) and neural stem cells (hNSCs) via directed differentiation. In both hMSCs and hNSCs, RAP1 not only negatively regulated telomere length but also acted as a transcriptional regulator of RELN by tuning the methylation status of its gene promoter. RAP1 deficiency enhanced self-renewal and delayed senescence in hMSCs, but not in hNSCs, suggesting complicated lineage-specific effects of RAP1 in adult stem cells.Altogether, these results demonstrate for the first time that RAP1 plays both telomeric and nontelomeric roles in regulating human stem cell homeostasis.
Multiple sgRNAs facilitate base editingmediated i-stop to induce complete and precise gene disruption
Kun Jia, Zongyang Lu, Fei Zhou, Zhiqi Xiong, Rui Zhang, Zhiwei Liu, Yu'e Ma, Lei He, Cong Li, Zhen Zhu, Dejing Pan, Zhengxing Lian
 doi: 10.1007/s13238-019-0611-6
Reciprocal regulation between lunapark and atlastin facilitates ER three-way junction formation
Xin Zhou, Yu He, Xiaofang Huang, Yuting Guo, Dong Li, Junjie Hu
 doi: 10.1007/s13238-018-0595-7
Three-way junctions are characteristic structures of the tubular endoplasmic reticulum (ER) network. Junctions are formed through atlastin (ATL)-mediated membrane fusion and stabilized by lunapark (Lnp). However, how Lnp is preferentially enriched at three-way junctions remains elusive. Here, we showed that Lnp loses its junction localization when ATLs are deleted. Reintroduction of ATL1 R77A and ATL3, which have been shown to cluster at the junctions, but not wild-type ATL1, relocates Lnp to the junctions. Mutations in the N-myristoylation site or hydrophobic residues in the coiled coil (CC1) of Lnp N-terminus (NT) cause mis-targeting of Lnp. Conversely, deletion of the lunapark motif in the C-terminal zinc finger domain, which affects the homooligomerization of Lnp, does not alter its localization. Purified Lnp-NT attaches to the membrane in a myristoylation-dependent manner. The mutation of hydrophobic residues in CC1 does not affect membrane association, but compromises ATL interactions. In addition, Lnp-NT inhibits ATL-mediated vesicle fusion in vitro. These results suggest that CC1 in Lnp-NT contacts junction-enriched ATLs for proper localization; subsequently, further ATL activity is limited by Lnp after the junction is formed. The proposed mechanism ensures coordinated actions of ATL and Lnp in generating and maintaining three-way junctions.
Immune regulation by protein ubiquitination: roles of the E3 ligases VHL and Itch
Daisuke Aki, Qian Li, Hui Li, Yun-Cai Liu, Jee Ho Lee
 doi: 10.1007/s13238-018-0586-8
Protein ubiquitination is an important means of posttranslational modification which plays an essential role in the regulation of various aspects of leukocyte development and function. The specificity of ubiquitin tagging to a protein substrate is determined by E3 ubiquitin ligases via defined E3-substrate interactions. In this review, we will focus on two E3 ligases, VHL and Itch, to discuss the latest progress in understanding their roles in the differentiation and function of CD4+ T helper cell subsets, the stability of regulatory T cells, effector function of CD8+ T cells, as well as the development and maturation of innate lymphoid cells. The biological implications of these E3 ubiquitin ligases will be highlighted in the context of normal and dysregulated immune responses including the control of homeostasis, inflammation, auto-immune responses and anti-tumor immunity. Further elucidation of the ubiquitin system in immune cells will help in the design of new therapeutic interventions for human immunological diseases and cancer.
The zinc transporter Slc39a5 controls glucose sensing and insulin secretion in pancreatic β-cells via Sirt1-and Pgc-1α-mediated regulation of Glut2
Xinhui Wang, Hong Gao, Wenhui Wu, Enjun Xie, Yingying Yu, Xuyan He, Jin Li, Wanru Zheng, Xudong Wang, Xizhi Cao, Zhuoxian Meng, Ligong Chen, Junxia Min, Fudi Wang
 doi: 10.1007/s13238-018-0580-1
Zinc levels are high in pancreatic β-cells, and zinc is involved in the synthesis, processing and secretion of insulin in these cells. However, precisely how cellular zinc homeostasis is regulated in pancreatic β-cells is poorly understood. By screening the expression of 14 Slc39a metal importer family member genes, we found that the zinc transporter Slc39a5 is significantly downregulated in pancreatic β-cells in diabetic db/db mice, obese ob/ob mice and high-fat diet-fed mice. Moreover, β-cell-specific Slc39a5 knockout mice have impaired insulin secretion. In addition, Slc39a5-deficient pancreatic islets have reduced glucose tolerance accompanied by reduced expression of Pgc-1α and its downstream target gene Glut2. The down-regulation of Glut2 in Slc39a5-deficient islets was rescued using agonists of Sirt1, Pgc-1α and Ppar-γ. At the mechanistic level, we found that Slc39a5-mediated zinc influx induces Glut2 expression via Sirt1-mediated Pgc-1α activation. These findings suggest that Slc39a5 may serve as a possible therapeutic target for diabetes-related conditions.
Current issue
  • ISSN1674-800X
  • EISSN1674-8018
  • IF (2017) 6.228

Microbiota and Human Health

May 2018
Volume 9
Issue 5
pp: 395-510

Metabolism and Disease

May 2018
Volume 9
Issue 2
pp: 141-237

Therapeutic Antibodies

May 2018
Volume 9
Issue 1
pp: 1-139


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