2016 Vol. 7(6)

Pursue the truth, devote to education: Chen Hua-Kui, a respectable educator and pioneer of China's soil microbiology
Doudou Chen, Han Zhang, Huan Liu
2016, 7(6): 389-390. doi: 10.1007/s13238-016-0270-9
Research articles
Homocysteine activates T cells by enhancing endoplasmic reticulum-mitochondria coupling and increasing mitochondrial respiration
Juan Feng, Silin Lü, Yanhong Ding, Ming Zheng, Xian Wang
2016, 7(6): 391-402. doi: 10.1007/s13238-016-0245-x
Hyperhomocysteinemia (HHcy) accelerates atherosclerosis by increasing proliferation and stimulating cytokine secretioninTcells. However, whether homocysteine (Hcy)-mediated T cell activation is associated with metabolic reprogramming is unclear. Here, our in vivo and in vitro studies showed that Hcy-stimulated splenic T-cell activation in mice was accompanied by increased levels of mitochondrial reactive oxygen species (ROS) and calcium, mitochondrial mass and respiration. Inhibiting mitochondrial ROS production and calcium signals or blocking mitochondrial respiration largely blunted Hcy-induced T-cell interferon γ (IFN-γ) secretion and proliferation. Hcy also enhanced endoplasmic reticulum (ER) stress in T cells, and inhibition of ER stress with 4-phenylbutyric acid blocked Hcy-induced T-cell activation. Mechanistically, Hcy increased ER-mitochondria coupling, and uncoupling ER-mitochondria by the microtubule inhibitor nocodazole attenuated Hcy-stimulated mitochondrial reprogramming, IFN-γ secretion and proliferation in T cells, suggesting that juxtaposition of ER and mitochondria is required for Hcy-promoted mitochondrial function and T-cell activation. In conclusion, Hcy promotes T-cell activation by increasing ER-mitochondria coupling and regulating metabolic reprogramming.
Structural insights into the regulatory mechanism of the Pseudomonas aeruginosa YfiBNR system
Min Xu, Xuan Yang, Xiu-An Yang, Lei Zhou, Tie-Zheng Liu, Zusen Fan, Tao Jiang
2016, 7(6): 403-416. doi: 10.1007/s13238-016-0264-7
YfiBNR is a recently identified bis-(3'-5')-cyclic dimeric GMP (c-di-GMP) signaling system in opportunistic pathogens. It is a key regulator of biofilm formation, which is correlated with prolonged persistence of infection and antibiotic drug resistance. In response to cell stress, YfiB in the outer membrane can sequester the periplasmic protein YfiR, releasing its inhibition of YfiN on the inner membrane and thus provoking the diguanylate cyclase activity of YfiN to induce c-di-GMP production. However, the detailed regulatory mechanism remains elusive. Here, we report the crystal structures of YfiB alone and of an active mutant YfiBL43P complexed with YfiR with 2:2 stoichiometry. Structural analyses revealed that in contrast to the compact conformation of the dimeric YfiB alone, YfiBL43P adopts a stretched conformation allowing activated YfiB to penetrate the peptidoglycan (PG) layer and access YfiR. YfiBL43P shows a more compact PG-binding pocket and much higher PG binding affinity than wild-type YfiB, suggesting a tight correlation between PG binding and YfiB activation. In addition, our crystallographic analyses revealed that YfiR binds Vitamin B6 (VB6) or L-Trp at a YfiB-binding site and that both VB6 and L-Trp are able to reduce YfiBL43P-induced biofilm formation. Based on the structural and biochemical data, we propose an updated regulatory model of the YfiBNR system.
Deacetylation of TFEB promotes fibrillar Aβ degradation by upregulating lysosomal biogenesis in microglia
Jintao Bao, Liangjun Zheng, Qi Zhang, Xinya Li, Xuefei Zhang, Zeyang Li, Xue Bai, Zhong Zhang, Wei Huo, Xuyang Zhao, Shujiang Shang, Qingsong Wang, Chen Zhang, Jianguo Ji
2016, 7(6): 417-433. doi: 10.1007/s13238-016-0269-2
Microglia play a pivotal role in clearance of Aβ by degrading them in lysosomes, countering amyloid plaque pathogenesis in Alzheimer's disease (AD). Recent evidence suggests that lysosomal dysfunction leads to insufficient elimination of toxic protein aggregates. We tested whether enhancing lysosomal function with transcription factor EB (TFEB), an essential regulator modulating lysosomal pathways, would promote Aβ clearance in microglia. Here we show that microglial expression of TFEB facilitates fibrillar Aβ (fAβ) degradation and reduces deposited amyloid plaques, which are further enhanced by deacetylation of TFEB. Using mass spectrometry analysis, we firstly confirmed acetylation as a previously unreported modification of TFEB and found that SIRT1 directly interacted with and deacetylated TFEB at lysine residue 116. Subsequently, SIRT1 overexpression enhanced lysosomal function and fAβ degradation by upregulating transcriptional levels of TFEB downstream targets, which could be inhibited when TFEB was knocked down. Furthermore, overexpression of deacetylated TFEB at K116R mutant in microglia accelerated intracellular fAβ degradation by stimulating lysosomal biogenesis and greatly reduced the deposited amyloid plaques in the brain slices of APP/PS1 transgenic mice. Our findings reveal that deacetylation of TFEB could regulate lysosomal biogenesis and fAβ degradation, making microglial activation of TFEB a possible strategy for attenuating amyloid plaque deposition in AD.
MiR-29b suppresses the proliferation and migration of osteosarcoma cells by targeting CDK6
Kegan Zhu, Lei Liu, Junliang Zhang, Yanbo Wang, Hongwei Liang, Gentao Fan, Zhenhuan Jiang, Chen-Yu Zhang, Xi Chen, Guangxin Zhou
2016, 7(6): 434-444. doi: 10.1007/s13238-016-0277-2
Osteosarcoma is the most common primary sarcoma of bone, and it is a leading cause of cancer death among adolescents and young adults. However, the molecular mechanism underlying osteosarcoma carcinogenesis remains poorly understood. Recently, cyclin-dependent kinase 6 (CDK6) was identified as an important oncogene. We found that CDK6 protein level, rather than CDK6 mRNA level, is much higher in osteosarcoma tissues than in normal adjacent tissues, which indicates a post-transcriptional mechanism involved in CDK6 regulation in osteosarcoma. MiRNAs are small noncoding RNAs that repress gene expression at the posttranscriptional level and have widely been shown to play important roles in many human cancers. In this study, we investigated the role of miR-29b as a novel regulator of CDK6 using bioinformatics methods. We demonstrated that CDK6 can be downregulated by miR-29b via binding to the 3'-UTR region in osteosarcoma cells. Furthermore, we identified an inverse correlation between miR-29b and CDK6 protein levels in osteosarcoma tissues. Finally, we examined the function of miR-29b-driven repression of CDK6 expression in osteosarcoma cells. The results revealed that miR-29b acts as a tumor suppressor of osteosarcoma by targeting CDK6 in the proliferation and migration processes. Taken together, our results highlight an important role for miR-29b in the regulation of CDK6 in osteosarcoma and may open new avenues for future osteosarcoma therapies.
Phorbol myristate acetate suppresses breast cancer cell growth via down-regulation of P-Rex1 expression
Chuu-Yun A. Wong, Haihong Jiang, Peter W. Abel, Margaret A. Scofield, Yan Xie, Taotao Wei, Yaping Tu
2016, 7(6): 445-449. doi: 10.1007/s13238-016-0261-x
The crystal structure of Zika virus helicase: basis for antiviral drug design
Hongliang Tian, Xiaoyun Ji, Xiaoyun Yang, Wei Xie, Kailin Yang, Cheng Chen, Chen Wu, Heng Chi, Zhongyu Mu, Zefang Wang, Haitao Yang
2016, 7(6): 450-454. doi: 10.1007/s13238-016-0275-4
Flotillin-1 downregulates K+ current by directly coupling with Kv2.1 subunit
Rui Liu, Guang Yang, Meng-Hua Zhou, Yu He, Yan-Ai Mei, Yu Ding
2016, 7(6): 455-460. doi: 10.1007/s13238-016-0276-3
Highly diversified Zika viruses imported to China, 2016
Yanjun Zhang, Wenxian Chen, Gary Wong, Yuhai Bi, Juying Yan, Yi Sun, Enfu Chen, Hao Yan, Xiuyu Lou, Haiyan Mao, Shichang Xia, George F. Gao, Weifeng Shi, Zhiping Chen
2016, 7(6): 461-464. doi: 10.1007/s13238-016-0274-5
Erratum to:Crystal structures of GI.8 Boxer virus P dimers in complex with HBGAs, a novel evolutionary path selected by the Lewis epitope
Ning Hao, Yutao Chen, Ming Xia, Ming Tan, Wu Liu, Xiaotao Guan, Xi Jiang, Xuemei Li, Zihe Rao
2016, 7(6): 465-465. doi: 10.1007/s13238-016-0266-5

Current Issue

March, 2019

Volume 10, Issue 3

Pages 157-233

About the cover

Metastasis is the leading cause of human cancer deaths.Unfortunately, no approved drugs are available for antimetastatic treatment. In this study, high-throughputsequencing-based high-throughput screening (HTS2) anda breast cancer lung metastasis (BCLM)-associated genesignature were combined to discover anti-metastatic drugs.After screening of thousands of compounds, Shao et al.identifed Ponatinib as a BCLM inhibitor. Ponatinib signifcantlyinhibited the migration and mammosphere formation of breastcancer cells in vitro and blocked BCLM in multiple mousemodels. This study may facilitate the therapeutic treatment ofBCLM as well as other metastases.

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

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