2011 Vol. 2(1)

A strong start, a promising future
Zihe Rao
2011, 2(1): 1-1. doi: 10.1007/s13238-011-1001-x
News and views
Smurfs have “fused” into the asymmetric division of stem cells
Steven Y. Cheng, Ying E. Zhang
2011, 2(1): 2-4. doi: 10.1007/s13238-011-1005-6
The 1956 Qingdao Meeting on Genetics: an important turning point of Chinese biology
Ming Li, Le Kang
2011, 2(1): 5-6. doi: 10.1007/s13238-011-1011-8
When MAGE meets RING: insights into biological functions of MAGE proteins
Yue Feng, Jinlan Gao, Maojun Yang
2011, 2(1): 7-12. doi: 10.1007/s13238-011-1002-9
The melanoma antigen (MAGE) family proteins are well known as tumor-specific antigens and comprise more than 60 genes, which share a conserved MAGE homology domain (MHD). Type I MAGEs are highly expressed cancer antigens, and they play an important role in tumorigenesis and cancer cell survival. Recently, several MAGE proteins were identified to interact with RING domain proteins, including a sub-family of E3 ubiquitin ligases. The binding mode between MAGEs and RING proteins was investigated and one important structure of these MAGE-RING complexes was solved:the MAGE-G1-NSE1 complex. Structural and biochemical studies indicated that MAGE proteins could adjust the E3 ubiquitin ligase activity of its cognate RING partner both in vitro and in vivo. However, the underlying mechanism was not fully understood. Here, we review these exciting advances in the studies on MAGE family, suggest potential mechanisms by which MAGEs activate the E3 activity of their binding RING proteins and highlight the anticancer potential of this family proteins.
Small GTPases and cilia
Yujie Li, Jinghua Hu
2011, 2(1): 13-25. doi: 10.1007/s13238-011-1004-7
Small GTPases are key molecular switches that bind and hydrolyze GTP in diverse membrane-and cytoskeletonrelated cellular processes. Recently, mounting evidences have highlighted the role of various small GTPases, including the members in Arf/Arl, Rab, and Ran subfamilies, in cilia formation and function. Once overlooked as an evolutionary vestige, the primary cilium has attracted more and more attention in last decade because of its role in sensing various extracellular signals and the association between cilia dysfunction and a wide spectrum of human diseases, now called ciliopathies. Here we review recent advances about the function of small GTPases in the context of cilia, and the correlation between the functional impairment of small GTPases and ciliopathies. Understanding of these cellular processes is of fundamental importance for broadening our view of cilia development and function in normal and pathological states and for providing valuable insights into the role of various small GTPases in disease processes, and their potential as therapeutic targets.
Structure and function of interleukin-17 family cytokines
Xiaoping Zhang, Pornpimon Angkasekwinai, Chen Dong, Hong Tang
2011, 2(1): 26-40. doi: 10.1007/s13238-011-1006-5
The recently identified interleukin-17 (IL-17) cytokines family, which comprises six members in mammals (IL-17A-F), plays essential roles in the host immunity against infectious diseases and chronic inflammatory diseases. The three-dimensional structures containing IL-17A or IL-17F have become available and revealed the unique structural features of IL-17s as well as their receptors. Molecular modeling in this review shows that IL-17s may adopt a "cysteine knot" fold commonly seen in nerve growth factor (NGF) and other neurotrophins. Further modeling analysis unmasks a signature interaction feature of the IL-17F/IL-17RA complex, where a small loop of IL-17RA slots into the deep groove of the interface of IL-17F homodimer. This is quite different from the interaction between the best known four-helix cytokines and their cognate receptors. On the other hand, structure of IL-17A and its monoclonal antibody (CAT-2200) shows that, albeit that the antigenic epitope of IL-17A resides outside of the IL-17A homodimer interface, its physical proximity to the receptor binding groove may explain that antibody blockage would be achieved by interfering with the ligand-receptor interaction. This review is to summarize the advance in understanding the structure and function of IL-17 family cytokines, focusing mainly on IL-17A, IL-17F and IL-17E, in the hope of gaining better knowledge of immunotherapeutic strategies against various inflammatory diseases.
Generation of glyco-engineered BY2 cell lines with decreased expression of plant-specific glycoepitopes
Bo-jiao Yin, Ting Gao, Nuo-yan Zheng, Yin Li, San-yuan Tang, Li-ming Liang, Qi XIE
2011, 2(1): 41-47. doi: 10.1007/s13238-011-1007-4
Plants are known to be efficient hosts for the production of mammalian therapeutic proteins. However, plants produce complex N-glycans bearing β1,2-xylose and core α1,3-fucose residues, which are absent in mammals. The immunogenicity and allergenicity of plant-specific Nglycans is a key concern in mammalian therapy. In this study, we amplified the sequences of 2 plant-specific glycosyltransferases from Nicotiana tabacum L. cv Bright Yellow 2 (BY2), which is a well-established cell line widely used for the expression of therapeutic proteins. The expression of the endogenous xylosyltranferase (XylT) and fucosyltransferase (FucT) was downregulated by using RNA interference (RNAi) strategy. The xylosylated and core fucosylated N-glycans were significantly, but not completely, reduced in the glycoengineered lines. However, these RNAi-treated cell lines were stable and viable and did not exhibit any obvious phenotype. Therefore, this study may provide an effective and promising strategy to produce recombinant glycoproteins in BY2 cells with humanized N-glycoforms to avoid potential immunogenicity.
Research articles
Germ cell sex prior to meiosis in the rainbow trout
Mingyou Li, Qian Shen, Foong Mei Wong, Hongyan Xu, Ni Hong, Lingbing Zeng, Lin Liu, Qiwei Wei, Yunhan Hong
2011, 2(1): 48-54. doi: 10.1007/s13238-011-1003-8
Germ cells make two major decisions when they move from an indeterminate state to their final stage of gamete production. One decision is sexual commitment for sperm or egg production, and the other is to maintain mitotic division or entry into meiosis. It is unclear whether the two decisions are made as a single event or separate events, because there has been no evidence for the presence of germ cell sex prior to meiosis. Here we report direct evidence in the fish rainbow trout that gonia have distinct sexuality. We show that dazl expression occurs in both male and female gonia but exhibits differential intracellular distribution. More strikingly, we show that boule is highly expressed in male gonia but absent in female gonia. Therefore, mitotic gonia possess sex, sperm/egg decision and mitosis/meiosis decision are two independent events, and sperm/egg decision precedes mitosis/meiosis decision in rainbow trout, making this organism a unique vertebrate model for mechanistic understanding of germ cell sex differentiation and relationship between the two decisions.
A structural view of the conserved domain of rice stress-responsive NAC1
Qingfeng Chen, Quan Wang, Lizhong Xiong, Zhiyong Lou
2011, 2(1): 55-63. doi: 10.1007/s13238-011-1010-9
The importance of NAC (named as NAM, ATAF1, 2, and CUC2) proteins in plant development, transcription regulation and regulatory pathways involving proteinprotein interactions has been increasingly recognized. We report here the high resolution crystal structure of SNAC1 (stress-responsive NAC) NAC domain at 2.5 Å. Although the structure of the SNAC1 NAC domain shares a structural similarity with the reported structure of the ANAC NAC1 domain, some key features, especially relating to two loop regions which potentially take the responsibility for DNA-binding, distinguish the SNAC1 NAC domain from other reported NAC structures. Moreover, the dimerization of the SNAC1 NAC domain is demonstrated by both soluble and crystalline conditions, suggesting this dimeric state should be conserved in this type of NAC family. Additionally, we discuss the possible NAC-DNA binding model according to the structure and reported biological evidences.
hNUDT16: a universal decapping enzyme for small nucleolar RNA and cytoplasmic mRNA
Guangwen Lu, Jie Zhang, Yan Li, Zhixin Li, Na Zhang, Xiang Xu, Tingting Wang, Zhenhong Guan, George F. Gao, Jinghua Yan
2011, 2(1): 64-73. doi: 10.1007/s13238-011-1009-2
Human NUDT16 (hNUDT16) is a decapping enzyme initially identified as the human homolog to the Xenopus laevis X29. As a metalloenzyme, hNUDT16 relies on divalent cations for its cap-hydrolysis activity to remove m7GDP and m227GDP from RNAs. Metal also determines substrate specificity of the enzyme. So far, only U8 small nucleolar RNA (snoRNA) has been identified as the substrate of hNUDT16 in the presence of Mg2+. Here we demonstrate that besides U8, hNUDT16 can also actively cleave the m7GDP cap from mRNAs in the presence of Mg2+ or Mn2+. We further show that hNUDT16 does not preferentially recognize U8 or mRNA substrates by our cross-inhibition and quantitative decapping assays. In addition, our mutagenesis analysis identifies several key residues involved in hydrolysis and confirms the key role of the REXXEE motif in catalysis. Finally an investigation into the subcellular localization of hNUDT16 revealed its abundance in both cytoplasm and nucleus. These findings extend the substrate spectrum of hNUDT16 beyond snoRNAs to also include mRNA, demonstrating the pleiotropic decapping activity of hNUDT16.
HID-1 is a peripheral membrane protein primarily associated with the medial- and trans-Golgi apparatus
Lifen Wang, Yi Zhan, Eli Song, Yong Yu, Yaming Jiu, Wen Du, Jingze Lu, Pingsheng Liu, Pingyong Xu, Tao Xu
2011, 2(1): 74-85. doi: 10.1007/s13238-011-1008-3
Caenorhabditis elegans hid-1 gene was first identified in a screen for mutants with a high-temperature-induced dauer formation (Hid) phenotype. Despite the fact that the hid-1 gene encodes a novel protein (HID-1) which is highly conserved from Caenorhabditis elegans to mammals, the domain structure, subcellular localization, and exact function of HID-1 remain unknown. Previous studies and various bioinformatic softwares predicted that HID-1 contained many transmembrane domains but no known functional domain. In this study, we revealed that mammalian HID-1 localized to the medial- and trans-Golgi apparatus as well as the cytosol, and the localization was sensitive to brefeldin A treatment. Next, we demonstrated that HID-1 was a peripheral membrane protein and dynamically shuttled between the Golgi apparatus and the cytosol. Finally, we verified that a conserved N-terminal myristoylation site was required for HID-1 binding to the Golgi apparatus. We propose that HID-1 is probably involved in the intracellular trafficking within the Golgi region.

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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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