2016 Vol. 7(7)

Recollection
Ray Wu, fifth business or father of DNA sequencing?
Yu Xue, Yongbo Wang, Hui Shen
2016, 7(7): 467-470. doi: 10.1007/s13238-016-0271-8
Abstract:
Vantage points
How does a β-barrel integral membrane protein insert into the membrane?
Xuejun C. Zhang, Lei Han
2016, 7(7): 471-477. doi: 10.1007/s13238-016-0273-6
Abstract:
Research articles
Vitamin C alleviates aging defects in a stem cell model for Werner syndrome
Ying Li, Weizhou Zhang, Liang Chang, Yan Han, Liang Sun, Xiaojun Gong, Hong Tang, Zunpeng Liu, Huichao Deng, Yanxia Ye, Yu Wang, Jian Li, Jie Qiao, Jing Qu, Weiqi Zhang, Guang-Hui Liu
2016, 7(7): 478-488. doi: 10.1007/s13238-016-0278-1
Abstract:
Werner syndrome (WS) is a premature aging disorder that mainly affects tissues derived from mesoderm. We have recently developed a novel human WS model using WRN-deficient human mesenchymal stem cells (MSCs). This model recapitulates many phenotypic features of WS. Based on a screen of a number of chemicals, here we found that Vitamin C exerts most efficient rescue for many features in premature aging as shown in WRN-deficient MSCs, including cell growth arrest, increased reactive oxygen species levels, telomere attrition, excessive secretion of inflammatory factors, as well as disorganization of nuclear lamina and heterochromatin. Moreover, Vitamin C restores in vivo viability of MSCs in a mouse model. RNA sequencing analysis indicates that Vitamin C alters the expression of a series of genes involved in chromatin condensation, cell cycle regulation, DNA replication, and DNA damage repair pathways in WRN deficient MSCs. Our results identify Vitamin C as a rejuvenating factor for WS MSCs, which holds the potential of being applied as a novel type of treatment of WS.
MiR-130a regulates neurite outgrowth and dendritic spine density by targeting MeCP2
Yunjia Zhang, Mengmeng Chen, Zilong Qiu, Keping Hu, Warren McGee, Xiaoping Chen, Jianghong Liu, Li Zhu, Jane Y. Wu
2016, 7(7): 489-500. doi: 10.1007/s13238-016-0272-7
Abstract:
MicroRNAs (miRNAs) are critical for both development and function of the central nervous system. Significant evidence suggests that abnormal expression of miRNAs is associated with neurodevelopmental disorders. MeCP2 protein is an epigenetic regulator repressing or activating gene transcription by binding to methylated DNA. Both loss-of-function and gain-of-function mutations in the MECP2 gene lead to neurodevelopmental disorders such as Rett syndrome, autism and MECP2 duplication syndrome. In this study, we demonstrate that miR-130a inhibits neurite outgrowth and reduces dendritic spine density as well as dendritic complexity. Bioinformatics analyses, cell cultures and biochemical experiments indicate that miR-130a targets MECP2 and down-regulates MeCP2 protein expression. Furthermore, expression of the wild-type MeCP2, but not a lossof-function mutant, rescues the miR-130a-induced phenotype. Our study uncovers the MECP2 gene as a previous unknown target for miR-130a, supporting that miR-130a may play a role in neurodevelopment by regulating MeCP2. Together with data from other groups, our work suggests that a feedback regulatory mechanism involving both miR-130a and MeCP2 may serve to ensure their appropriate expression and function in neural development.
Cataract-causing mutation S228P promotes βB1-crystallin aggregation and degradation by separating two interacting loops in C-terminal domain
Liang-Bo Qi, Li-Dan Hu, Huihui Liu, Hai-Yun Li, Xiao-Yao Leng, Yong-Bin Yan
2016, 7(7): 501-515. doi: 10.1007/s13238-016-0284-3
Abstract:
β/γ-Crystallins are predominant structural proteins in the cytoplasm of lens fiber cells and share a similar fold composing of four Greek-key motifs divided into two domains. Numerous cataract-causing mutations have been identified in various β/γ-crystallins, but the mechanisms underlying cataract caused by most mutations remains uncharacterized. The S228P mutation in βB1-crystallin has been linked to autosomal dominant congenital nuclear cataract. Here we found that the S228P mutant was prone to aggregate and degrade in both of the human and E. coli cells. The intracellular S228P aggregates could be redissolved by lanosterol. The S228P mutation modified the refolding pathway of βB1-crystallin by affecting the formation of the dimeric intermediate but not the monomeric intermediate. Compared with native βB1-crystallin, the refolded S228P protein had less packed structures, unquenched Trp fluorophores and increased hydrophobic exposure. The refolded S228P protein was prone to aggregate at the physiological temperature and decreased the protective effect of βB1-crystallin on βA3-crystallin. Molecular dynamic simulation studies indicated that the mutation decreased the subunit binding energy and modified the distribution of surface electrostatic potentials. More importantly, the mutation separated two interacting loops in the C-terminal domain, which shielded the hydrophobic core from solvent in native βB1-crystallin. These two interacting loops are highly conserved in both of the N-and C-terminal domains of all β/γ-crystallins. We propose that these two interacting loops play an important role in the folding and structural stability of β/γ-crystallin domains by protecting the hydrophobic core from solvent access.
Crystal structure of a PP2A B56-BubR1 complex and its implications for PP2A substrate recruitment and localization
Jiao Wang, Zhizhi Wang, Tingting Yu, Huan Yang, David M. Virshup, Geert J. P. L. Kops, Sang Hyun Lee, Weihong Zhou, Xin Li, Wenqing Xu, Zihe Rao
2016, 7(7): 516-526. doi: 10.1007/s13238-016-0283-4
Abstract:
Protein phosphatase 2A (PP2A) accounts for the majority of total Ser/Thr phosphatase activities in most cell types and regulates many biological processes. PP2A holoenzymes contain a scaffold A subunit, a catalytic C subunit, and one of the regulatory/targeting B subunits. How the B subunit controls PP2A localization and substrate specificity, which is a crucial aspect of PP2A regulation, remains poorly understood. The kinetochore is a critical site for PP2A functioning, where PP2A orchestrates chromosome segregation through its interactions with BubR1. The PP2A-BubR1 interaction plays important roles in both spindle checkpoint silencing and stable microtubule-kinetochore attachment. Here we present the crystal structure of a PP2A B56-BubR1 complex, which demonstrates that a conserved BubR1 LxxIxE motif binds to the concave side of the B56 pseudo-HEAT repeats. The BubR1 motif binds to a groove formed between B56 HEAT repeats 3 and 4, which is quite distant from the B56 binding surface for PP2A catalytic C subunit and thus is unlikely to affect PP2A activity. In addition, the BubR1 binding site on B56 is far from the B56 binding site of shugoshin, another kinetochore PP2A-binding protein, and thus BubR1 and shugoshin can potentially interact with PP2A-B56 simultaneously. Our structural and biochemical analysis indicates that other proteins with the LxxIxE motif may also bind to the same PP2A B56 surface. Thus, our structure of the PP2A B56-BubR1 complex provides important insights into how the B56 subunit directs the recruitment of PP2A to specific targets.
Letters
Fructose promotes growth and antifungal activity of Penicillium citrinum
Chang-wen Wu, Xiaojun Wu, Chao Wen, Bo Peng, Xuan-xian Peng, Xinhua Chen, Hui Li
2016, 7(7): 527-532. doi: 10.1007/s13238-016-0280-7
Abstract:
Proteomic analysis of mTOR inhibitionmediated phosphorylation changes in ribosomal proteins and eukaryotic translation initiation factors
Xu Jiang, Shan Feng, Yuling Chen, Yun Feng, Haiteng Deng
2016, 7(7): 533-537. doi: 10.1007/s13238-016-0279-0
Abstract:
Interferon-related secretome from direct interaction between immune cells and tumor cells is required for upregulation of PD-L1 in tumor cells
Yuan-Qin Yang, Wen-Jie Dong, Xiao-Fei Yin, Yan-Ni Xu, Yu Yang, Jiao-Jiao Wang, Su-Jing Yuan, Jing Xiao, Jonathan Howard DeLong, Liang Chu, Hai-Neng Xu, XiuMei Zhou, Ru-Wei Wang, Ling Fang, Xin-Yuan Liu, Kang-Jian Zhang
2016, 7(7): 538-543. doi: 10.1007/s13238-016-0281-6
Abstract:

Current Issue

August, 2019

Volume 10, Issue 8

Pages 545-621

About the cover

Utilizing immunocompromised SCID mice after spinal cordinjury (SCI), we performed motor function, electrophysiology,histochemistry analyses and demonstrated that SCID micedisplayed improved CNS functional recovery compared toWT mice after SCI, while SCID mice without injury performedworse in Morris water maze test. Unbiased RNA-sequencinganalysis of spinal cord transcriptomes revealed that SCIDmice had reduced expression of immune function-relatedgenes and heightened expression of neural transmissionrelated genes both before and after SCI, indicating that notonly reduced inflammation after injury but also dampenedsteady-state immune function without injury heightened theneurotransmission program, resulting in better or worsebehavioral outcomes respectively, under pathological orphysiological conditions. This study revealed an interestingand intricate relationship between immune and neuralfunctions.

Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang Beijing 100101, China

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