2010 Vol. 1, No. 7

News and views
Insulin, longevity, and genetic analysis of metabolism
Steven Y Cheng
2010, 1(7): 605-606. doi: 10.1007/s13238-010-0080-4
Histones, histone chaperones and nucleosome assembly
Rebecca J. Burgess, Zhiguo Zhang
2010, 1(7): 607-612. doi: 10.1007/s13238-010-0086-y
Chromatin structure governs a number of cellular processes including DNA replication, transcription, and DNA repair. During DNA replication, chromatin structure including the basic repeating unit of chromatin, the nucleosome, is temporarily disrupted, and then reformed immediately after the passage of the replication fork. This coordinated process of nucleosome assembly during DNA replication is termed replication-coupled nucleosome assembly. Disruption of this process can lead to genome instability, a hallmark of cancer cells. Therefore, addressing how replication-coupled nucleosome assembly is regulated has been of great interest. Here, we review the current status of this growing field of interest, highlighting recent advances in understanding the regulation of this important process by the dynamic interplay of histone chaperones and histone modifications.
Bing Zhi: pioneer of modern biology in China
Ming Li, Le Kang
2010, 1(7): 613-615. doi: 10.1007/s13238-010-0081-3
A loop matters for FTO substrate selection
Zhifu Han, Ning Huang, Tianhui Niu, Jijie Chai
2010, 1(7): 616-620. doi: 10.1007/s13238-010-0082-2
Recent studies have unequivocally established the link between FTO and obesity. FTO was biochemically shown to belong to the AlkB-like family DNA/RNA demethylase. However, FTO differs from other AlkB members in that it has unique substrate specificity and contains an extended C-terminus with unknown functions. Insight into the substrate selection mechanism and a functional clue to the C-terminus of FTO were gained from recent structural and biochemical studies. These data would be valuable to design FTO-specific inhibitors that can be potentially translated into therapeutic agents for treatment of obesity or obesity-related diseases.
Engineering of a genome-reduced host: practical application of synthetic biology in the overproduction of desired secondary metabolites
Hong Gao, Ying Zhuo, Elizabeth Ashforth, Lixin Zhang
2010, 1(7): 621-626. doi: 10.1007/s13238-010-0073-3
Synthetic biology aims to design and build new biological systems with desirable properties, providing the foundation for the biosynthesis of secondary metabolites. The most prominent representation of synthetic biology has been used in microbial engineering by recombinant DNA technology. However, there are advantages of using a deleted host, and therefore an increasing number of biotechnology studies follow similar strategies to dissect cellular networks and construct genomereduced microbes. This review will give an overview of the strategies used for constructing and engineering reduced-genome factories by synthetic biology to improve production of secondary metabolites.
Recent advances in the understanding of the molecular mechanisms regulating platelet integrin αⅡbβ3 activation
Lanlan Tao, Yue Zhang, Xiaodong Xi, Nelly Kieffer
2010, 1(7): 627-637. doi: 10.1007/s13238-010-0089-8
Integrins are allosteric cell adhesion receptors that cycle from a low to a high affinity ligand binding state, a complex process of receptor activation that is of particular importance in blood cells such as platelets or leukocytes. Here we highlight recent progress in the understanding of the molecular pathways that regulate integrin activation in platelets and leukocytes, with a special focus on the structural changes in platelet integrin αⅡbβ3 brought about by key intracellular proteins, namely talin and kindlins, that are of crucial importance in the regulation of integrin function. Evidence that the small GTPase Rap1 and its guanine exchange factor CalDAG-GEF1, together with RIAM, a Rap1GTP adaptor protein, promote the interaction of talin with the integrin β subunit, has greatly contributed to fill the gap in our understanding of the signaling pathway from G-coupled agonist receptors and their phospholipase C-dependant second messengers, to integrin activation. Studies of patients with the rare blood cell disorder LAD-Ⅲ have contributed to the identification of kindlins as new co-regulators of the talin-dependent integrin activation process in platelets and leukocytes, underlining the relevance for the in-depth investigation of patients with rare genetic blood cell disorders.
Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting
Zhi Huang, Lin Cheng, Olga A. Guryanova, Qiulian Wu, Shideng Bao
2010, 1(7): 638-655. doi: 10.1007/s13238-010-0078-y
Glioblastomas (GBMs) are highly lethal primary brain tumors. Despite current therapeutic advances in other solid cancers, the treatment of these malignant gliomas remains essentially palliative. GBMs are extremely resistant to conventional radiation and chemotherapies. We and others have demonstrated that a highly tumorigenic subpopulation of cancer cells called GBM stem cells (GSCs) promotes therapeutic resistance. We also found that GSCs stimulate tumor angiogenesis by expressing elevated levels of VEGF and contribute to tumor growth, which has been translated into a useful therapeutic strategy in the treatment of recurrent or progressive GBMs. Furthermore, stem cell-like cancer cells (cancer stem cells) have been shown to promote metastasis. Although GBMs rarely metastasize beyond the central nervous system, these highly infiltrative cancers often invade into normal brain tissues preventing surgical resection, and GSCs display an aggressive invasive phenotype. These studies suggest that targeting GSCs may effectively reduce tumor recurrence and significantly improve GBM treatment. Recent studies indicate that cancer stem cells share core signaling pathways with normal somatic or embryonic stem cells, but also display critical distinctions that provide important clues into useful therapeutic targets. In this review, we summarize the current understanding and advances in glioma stem cell research, and discuss potential targeting strategies for future development of anti-GSC therapies.
Research articles
RNF152, a novel lysosome localized E3 ligase with pro-apoptotic activities
Songling Zhang, Wei Wu, Yanfang Wu, Jiyan Zheng, Talin Suo, Hong Tang, Jie Tang
2010, 1(7): 656-663. doi: 10.1007/s13238-010-0083-1
RING finger protein 152 (RNF152) is a novel RING finger protein and has not been well characterized. We report here that RNF152 is a canonical RING finger protein and has E3 ligase activity. It is polyubiqitinated partly through Lys-48-linked ubiquitin chains in vivo and this phenomenon is dependent on its RING finger domain and transmembrane domain. RNF152 is localized in lysosomes and co-localized with LAMP3, a lysosome marker. Moreover, over-expression of RNF152 in Hela cells induces apoptosis. These results suggest that RNF152 is a lysosome localized E3 ligase with pro-apoptotic activities. It is the first E3 ligase identified so far that is involved in lysosome-related apoptosis.
Specific interaction of hepatitis C virus glycoproteins with mannan binding lectin inhibits virus entry
Kristelle S. Brown, Michael J. Keogh, Ania M. Owsianka, Richard Adair, Arvind H. Patel, James N. Arnold, Jonathan K. Ball, Robert B. Sim, Alexander W. Tarr, Timothy P. Hickling
2010, 1(7): 664-674. doi: 10.1007/s13238-010-0088-9
Mannan-binding lectin (MBL) is a soluble innate immune protein that binds to glycosylated targets. MBL acts as an opsonin and activates complement, contributing to the destruction and clearance of infecting microorganisms. Hepatitis C virus (HCV) encodes two envelope glycoproteins E1 and E2, expressed as non-covalent E1/E2 heterodimers in the viral envelope. E1 and E2 are potential ligands for MBL. Here we describe an analysis of the interaction between HCV and MBL using recombinant soluble E2 ectodomain fragment, the full-length E1/E2 heterodimer, expressed in vitro, and assess the effect of this interaction on virus entry. A binding assay using antibody capture of full length E1/E2 heterodimers was used to demonstrate calcium dependent, saturating binding of MBL to HCV glycoproteins. Competition with various saccharides further confirmed that the interaction was via the lectin domain of MBL. MBL binds to E1/E2 representing a broad range of virus genotypes. MBL was shown to neutralize the entry into Huh-7 cells of HCV pseudoparticles (HCVpp) bearing E1/E2 from a wide range of genotypes. HCVpp were neutralized to varying degrees. MBL was also shown to neutralize an authentic cell culture infectious virus, strain JFH-1 (HCVcc). Furthermore, binding of MBL to E1/E2 was able to activate the complement system via MBL-associated serine protease 2. In conclusion, MBL interacts directly with HCV glycoproteins, which are present on the surface of the virion, resulting in neutralization of HCV particles.
Quantitative proteomic analysis of S-nitrosated proteins in diabetic mouse liver with ICAT switch method
Xu Zhang, Bo Huang, Xixi Zhou, Chang Chen
2010, 1(7): 675-687. doi: 10.1007/s13238-010-0087-x
In this study we developed a quantitative proteomic method named ICATswitch by introducing isotope-coded affinity tag (ICAT) reagents into the biotin-switch method, and used it to investigate S-nitrosation in the liver of normal control C57BL/6J mice and type 2 diabetic KK-Ay mice. We got fifty-eight S-nitrosated peptides with quantitative information in our research, among which thirty-seven had changed S-nitrosation levels in diabetic mouse liver. The S-nitrosated peptides belonged to fortyeight proteins (twenty-eight were new S-nitrosated proteins), some of which were new targets of S-nitrosation and known to be related with diabetes. S-nitrosation patterns were different between diabetic and normal mice. Gene ontology enrichment results suggested that S-nitrosated proteins are more abundant in amino acid metabolic processes. The network constructed for Snitrosated proteins by text-mining technology provided clues about the relationship between S-nitrosation and type 2 diabetes. Our work provides a new approach for quantifying S-nitrosated proteins and suggests that the integrative functions of S-nitrosation may take part in pathophysiological processes of type 2 diabetes.
Structures of the N-and C-terminal domains of MHV-A59 nucleocapsid protein corroborate a conserved RNA-protein binding mechanism in coronavirus
Yanlin Ma, Xiaohang Tong, Xiaoling Xu, Xuemei Li, Zhiyong Lou, Zihe Rao
2010, 1(7): 688-697. doi: 10.1007/s13238-010-0079-x
Coronaviruses are the causative agent of respiratory and enteric diseases in animals and humans. One example is SARS, which caused a worldwide health threat in 2003. In coronaviruses, the structural protein N (nucleocapsid protein) associates with the viral RNA to form the filamentous nucleocapsid and plays a crucial role in genome replication and transcription. The structure of Nterminal domain of MHV N protein also implicated its specific affinity with transcriptional regulatory sequence (TRS) RNA. Here we report the crystal structures of the two proteolytically resistant N-(NTD) and C-terminal (CTD) domains of the N protein from murine hepatitis virus (MHV). The structure of NTD in two different crystal forms was solved to 1.5 Å. The higher resolution provides more detailed structural information than previous reports, showing that the NTD structure from MHV shares a similar overall and topology structure with that of SARS-CoV and IBV, but varies in its potential surface, which indicates a possible difference in RNA-binding module. The structure of CTD was solved to 2.0-Å resolution and revealed a tightly intertwined dimer. This is consistent with analytical ultracentrifugation experiments, suggesting a dimeric assembly of the N protein. The similarity between the structures of these two domains from SARS-CoV, IBV and MHV corroborates a conserved mechanism of nucleocapsid formation for coronaviruses.