2015 Vol. 6(4)

News and views
Periostin: a potent chemotactic factor for recruiting tumor-associated macrophage
Tiantian Wu, Qi Luo, Gaoliang Ouyang
2015, 6(4): 235-237. doi: 10.1007/s13238-015-0141-9
Structural basis of PKM2 regulation
Weiwei Yang
2015, 6(4): 238-240. doi: 10.1007/s13238-015-0146-4
Three-dimensional regulation of transcription
Jun Cao, Zhengyu Luo, Qingyu Cheng, Qianlan Xu, Yan Zhang, Fei Wang, Yan Wu, Xiaoyuan Song
2015, 6(4): 241-253. doi: 10.1007/s13238-015-0135-7
Cells can adapt to environment and development by reconstructing their transcriptional networks to regulate diverse cellular processes without altering the underlying DNA sequences. These alterations, namely epigenetic changes, occur during cell division, differentiation and cell death. Numerous evidences demonstrate that epigenetic changes are governed by various types of determinants, including DNA methylation patterns, histone posttranslational modification signatures, histone variants, chromatin remodeling, and recently discovered chromosome conformation characteristics and noncoding RNAs (ncRNAs). Here, we highlight recent efforts on how the two latter epigenetic factors participate in the sophisticated transcriptional process and describe emerging techniques which permit us to uncover and gain insights into the fascinating genomic regulation.
Cholesterol metabolism and homeostasis in the brain
Juan Zhang, Qiang Liu
2015, 6(4): 254-264. doi: 10.1007/s13238-014-0131-3
Cholesterol is an essential component for neuronal physiology not only during development stage but also in the adult life. Cholesterol metabolism in brain is independent from that in peripheral tissues due to blood-brain barrier. The content of cholesterol in brain must be accurately maintained in order to keep brain function well. Defects in brain cholesterol metabolism has been shown to be implicated in neurodegenerative diseases, such as Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), and some cognitive deficits typical of the old age. The brain contains large amount of cholesterol, but the cholesterol metabolism and its complex homeostasis regulation are currently poorly understood. This review will seek to integrate current knowledge about the brain cholesterol metabolism with molecular mechanisms.
Mass spectrometry-based proteomic approaches to study pathogenic bacteria-host interactions
Yufei Yang, Mo Hu, Kaiwen Yu, Xiangmei Zeng, Xiaoyun Liu
2015, 6(4): 265-274. doi: 10.1007/s13238-015-0136-6
Elucidation of molecular mechanisms underlying hostpathogen interactions is important for control and treatment of infectious diseases worldwide. Within the last decade, mass spectrometry (MS)-based proteomics has become a powerful and effective approach to better understand complex and dynamic host-pathogen interactions at the protein level. Herein we will review the recent progress in proteomic analyses towards bacterial infection of their mammalian host with a particular focus on enteric pathogens. Large-scale studies of dynamic proteomic alterations during infection will be discussed from the perspective of both pathogenic bacteria and host cells.
Research articles
Structural insight into mechanisms for dynamic regulation of PKM2
Ping Wang, Chang Sun, Tingting Zhu, Yanhui Xu
2015, 6(4): 275-287. doi: 10.1007/s13238-015-0132-x
Pyruvate kinase isoform M2 (PKM2) converts phospho-enolpyruvate (PEP) to pyruvate and plays an important role in cancer metabolism. Here, we show that post-translational modifications and a patient-derived mutation regulate pyruvate kinase activity of PKM2 through modulating the conformation of the PKM2 tetramer. We determined crystal structures of human PKM2 mutants and proposed a "seesaw" model to illustrate conformational changes between an inactive T-state and an active R-state tetramers of PKM2. Biochemical and structural analyses demonstrate that PKM2Y105E (phosphorylation mimic of Y105) decreases pyruvate kinase activity by inhibiting FBP (fructose 1,6-bisphosphate)-induced R-state formation, and PKM2K305Q (acetylation mimic of K305) abolishes the activity by hindering tetramer formation. K422R, a patient-derived mutation of PKM2, favors a stable, inactive T-state tetramer because of strong intermolecular interactions. Our study reveals the mechanism for dynamic regulation of PKM2 by posttranslational modifications and a patient-derived mutation and provides a structural basis for further investigation of other modifications and mutations of PKM2 yet to be discovered.
Phosphorylation of Atg31 is required for autophagy
Wenzhi Feng, Tong Wu, Xiaoyu Dan, Yuling Chen, Lin Li, She Chen, Di Miao, Haiteng Deng, Xinqi Gong, Li Yu
2015, 6(4): 288-296. doi: 10.1007/s13238-015-0138-4
Autophagy is an evolutionarily conserved cellular process which degrades intracellular contents. The Atg17-Atg31-Atg29 complex plays a key role in autophagy induction by various stimuli. In yeast, autophagy occurs with autophagosome formation at a special site near the vacuole named the pre-autophagosomal structure (PAS). The Atg17-Atg31-Atg29 complex forms a scaffold for PAS organization, and recruits other autophagy-related (Atg) proteins to the PAS. Here, we show that Atg31 is a phosphorylated protein. The phosphorylation sites on Atg31 were identified by mass spectrometry. Analysis of mutants in which the phosphorylated amino acids were replaced by alanine, either individually or in various combinations, identified S174 as the functional phosphorylation site. An S174A mutant showed a similar degree of autophagy impairment as an Atg31 deletion mutant. S174 phosphorylation is required for autophagy induced by various autophagy stimuli such as nitrogen starvation and rapamycin treatment. Mass spectrometry analysis showed that S174 is phosphorylated constitutively, and expression of a phosphorylation-mimic mutant (S174D) in the Atg31 deletion strain restores autophagy. In the S174A mutant, Atg9-positive vesicles accumulate at the PAS. Thus, S174 phosphorylation is required for formation of autophagosomes, possibly by facilitating the recycling of Atg9 from the PAS. Our data demonstrate the role of phosphorylation of Atg31 in autophagy.
Human BDCA2+CD123+CD56+ dendritic cells (DCs) related to blastic plasmacytoid dendritic cell neoplasm represent a unique myeloid DC subset
Haisheng Yu, Peng Zhang, Xiangyun Yin, Zhao Yin, Quanxing Shi, Ya Cui, Guanyuan Liu, Shouli Wang, Pier Paolo Piccaluga, Taijiao Jiang, Liguo Zhang
2015, 6(4): 297-306. doi: 10.1007/s13238-015-0140-x
Dendritic cells (DCs) comprise two functionally distinct subsets:plasmacytoid DCs (pDCs) and myeloid DCs (mDCs). pDCs are specialized in rapid and massive secretion of type I interferon (IFN-I) in response to nucleic acids through Toll like receptor (TLR)-7 or TLR-9. In this report, we characterized a CD56+ DC population that express typical pDC markers including CD123 and BDCA2 but produce much less IFN-I comparing with pDCs. In addition, CD56+ DCs cluster together with mDCs but not pDCs by genome-wide transcriptional profiling. Accordingly, CD56+ DCs functionally resemble mDCs by producing IL-12 upon TLR4 stimulation and priming naïve T cells without prior activation. These data suggest that the CD56+ DCs represent a novel mDC subset mixed with some pDC features. A CD4+CD56+ hematological malignancy was classified as blastic plasmacytoid dendritic cell neoplasm (BPDCN) due to its expression of characteristic molecules of pDCs. However, we demonstrated that BPDCN is closer to CD56+ DCs than pDCs by global gene-expression profiling. Thus, we propose that the CD4+CD56+ neoplasm may be a tumor counterpart of CD56+ mDCs but not pDCs.
Human atlastin GTPases mediate differentiated fusion of endoplasmic reticulum membranes
Xiaoyu Hu, Fuyun Wu, Sha Sun, Wenying Yu, Junjie Hu
2015, 6(4): 307-311. doi: 10.1007/s13238-015-0139-3

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.

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