2013 Vol. 4, No. 6

The role of gut microbiota in the gut-brain axis: current challenges and perspectives
Xiao Chen, Roshan D'Souza, Seong-Tshool Hong
2013, 4(6): 403-414. doi: 10.1007/s13238-013-3017-x
Brain and the gastrointestinal (GI) tract are intimately connected to form a bidirectional neurohumoral communication system. The communication between gut and brain, knows as the gut-brain axis, is so well established that the functional status of gut is always related to the condition of brain. The researches on the gut-brain axis were traditionally focused on the psychological status affecting the function of the GI tract. However, recent evidences showed that gut microbiota communicates with the brain via the gut-brain axis to modulate brain development and behavioral phenotypes. These recent findings on the new role of gut microbiota in the gut-brain axis implicate that gut microbiota could associate with brain functions as well as neurological diseases via the gut-brain axis. To elucidate the role of gut microbiota in the gut-brain axis, precise identification of the composition of microbes constituting gut microbiota is an essential step. However, identification of microbes constituting gut microbiota has been the main technological challenge currently due to massive amount of intestinal microbes and the difficulties in culture of gut microbes. Current methods for identification of microbes constituting gut microbiota are dependent on omics analysis methods by using advanced high tech equipment. Here, we review the association of gut microbiota with the gut-brain axis, including the pros and cons of the current high throughput methods for identification of microbes constituting gut microbiota to elucidate the role of gut microbiota in the gut-brain axis.
Induced pluripotency and direct reprogramming: a new window for treatment of neurodegenerative diseases
Rui Li, Ye Bai, Tongtong Liu, Xiaoqun Wang, Qian Wu
2013, 4(6): 415-424. doi: 10.1007/s13238-013-2089-y
Human embryonic stem cells (hESCs) are pluripotent cells that have the ability of unlimited self-renewal and can be differentiated into different cell lineages, including neural stem (NS) cells. Diverse regulatory signaling pathways of neural stem cells differentiation have been discovered, and this will be of great benefit to uncover the mechanisms of neuronal differentiation in vivo and in vitro. However, the limitations of hESCs resource along with the religious and ethical concerns impede the progress of ESCs application. Therefore, the induced pluripotent stem cells (iPSCs) via somatic cell reprogramming have opened up another new territory for regenerative medicine. iPSCs now can be derived from a number of lineages of cells, and are able to differentiate into certain cell types, including neurons. Patient-specific iPSCs are being used in human neurodegenerative disease modeling and drug screening. Furthermore, with the development of somatic direct reprogramming or lineage reprogramming technique, a more effective approach for regenerative medicine could become a complement for iPSCs.
Cellular localization of NLRP3 inflammasome
Yan Wang, Chen Yang, Kairui Mao, Shuzhen Chen, Guangxun Meng, Bing Sun
2013, 4(6): 425-431. doi: 10.1007/s13238-013-2113-2
Inflammasome is a large protein complex activated upon cellular stress or microbial infection, which triggers maturation of pro-inflammatory cytokines interleukin-1β and interleukin-18 through caspase-1 activation. Nod-like receptor family protein 3 (NLRP3) is the most characterized inflammasome activated by various stimuli. However, the mechanism of its activation is unclear and its exact cellular localization is still unknown. We examined the potential co-localization of NLRP3 inflammasome with mitochondria and seven other organelles under adenosine triphosphate, nigericin or monosodium urate stimulation in mouse peritoneal macrophages using confocal microscopy approach. Our results revealed that the activated endogenous apoptosis-associated speck-like protein containing a CARD (ASC) pyroptosome forms in the cytoplasm and co-localizes with NLRP3 and caspase-1, but not with any of the organelles screened. This study indicates that the ASC pyroptosome universally localizes within the cytoplasm rather than with any specific organelles.
Research article
Flexible interwoven termini determine the thermal stability of thermosomes
Kai Zhang, Li Wang, Yanxin Liu, Kwok-Yan Chan, Xiaoyun Pang, Klaus Schulten, Zhiyang Dong, Fei Sun
2013, 4(6): 432-444. doi: 10.1007/s13238-013-3026-9
Group Ⅱ chaperonins, which assemble as double-ring complexes, assist in the refolding of nascent peptides or denatured proteins in an ATP-dependent manner. The molecular mechanism of group Ⅱ chaperonin assembly and thermal stability is yet to be elucidated. Here, we selected the group Ⅱ chaperonins (cpn-α and cpn-β), also called thermosomes, from Acidianus tengchongensis and investigated their assembly and thermal stability. We found that the binding of ATP or its analogs contributed to the successful assembly of thermosomes and enhanced their thermal stabilities. Cpn-β is more thermally stable than cpn-α, while the thermal stability of the hetero thermosome cpn-αβ is intermediate. Cryo-electron microscopy reconstructions of cpn-α and cpn-β revealed the interwoven densities of their non-conserved flexible N/C-termini around the equatorial planes. The deletion or swapping of their termini and pH-dependent thermal stability assays revealed the key role of the termini electrostatic interactions in the assembly and thermal stability of the thermosomes.
The nucleoprotein of severe fever with thrombocytopenia syndrome virus processes a stable hexameric ring to facilitate RNA encapsidation
Honggang Zhou, Yuna Sun, Ying Wang, Min Liu, Chao Liu, Wenming Wang, Xiang Liu, Le Li, Fei Deng, Hualin Wang, Yu Guo, Zhiyong Lou
2013, 4(6): 445-455. doi: 10.1007/s13238-013-3901-4
Severe fever with thrombocytopenia syndrome virus (SFTSV), a member of the Phlebovirus genus from the Bunyaviridae family endemic to China, is the causative agent of life-threatening severe fever with thrombocytopenia syndrome (SFTS), which features high fever and hemorrhage. Similar to other negative-sense RNA viruses, SFTSV encodes a nucleocapsid protein (NP) that is essential for viral replication. NP facilitates viral RNA encapsidation and is responsible for the formation of ribonucleoprotein complex. However, recent studies have indicated that NP from Phlebovirus members behaves in inhomogeneous oligomerization states. In the present study, we report the crystal structure of SFTSV NP at 2.8 Å resolution and demonstrate the mechanism by which it processes a ringshaped hexameric form to accomplish RNA encapsidation. Key residues essential for oligomerization are identified through mutational analysis and identified to have a significant impact on RNA binding, which suggests that correct formation of highly ordered oligomers is a critical step in RNA encapsidation. The findings of this work provide new insights into the discovery of new antiviral reagents for Phlebovirus infection.
Cytosolic Ca2+ as a multifunctional modulator is required for spermiogenesis in Ascaris suum
Yunlong Shang, Lianwan Chen, Zhiyu Liu, Xia Wang, Xuan Ma, Long Miao
2013, 4(6): 456-466. doi: 10.1007/s13238-013-3019-8
The dynamic polar polymers actin filaments and microtubules are usually employed to provide the structural basis for establishing cell polarity in most eukaryotic cells. Radially round and immotile spermatids from nematodes contain almost no actin or tubulin, but still have the ability to break symmetry to extend a pseudopod and initiate the acquisition of motility powered by the dynamics of cytoskeleton composed of major sperm protein (MSP) during spermiogenesis (sperm activation). However, the signal transduction mechanism of nematode sperm activation and motility acquisition remains poorly understood. Here we show that Ca2+ oscillations induced by the Ca2+ release from intracellular Ca2+ store through inositol (1,4,5)-trisphosphate receptor are required for Ascaris suum sperm activation. The chelation of cytosolic Ca2+ suppresses the generation of a functional pseudopod, and this suppression can be relieved by introducing exogenous Ca2+ into sperm cells. Ca2+ promotes MSP-based sperm motility by increasing mitochondrial membrane potential and thus the energy supply required for MSP cytoskeleton assembly. On the other hand, Ca2+ promotes MSP disassembly by activating Ca2+/calmodulin-dependent serine/threonine protein phosphatase calcineurin. In addition, Ca2+/camodulin activity is required for the fusion of sperm-specific membranous organelle with the plasma membrane, a regulated exocytosis required for sperm motility. Thus, Ca2+ plays multifunctional roles during sperm activation in Ascaris suum.
Discovery of a novel gene involved in autolysis of Clostridium cells
Liejian Yang, Guanhui Bao, Yan Zhu, Hongjun Dong, Yanping Zhang, Yin Li
2013, 4(6): 467-474. doi: 10.1007/s13238-013-3025-x
Cell autolysis plays important physiological roles in the life cycle of clostridial cells. Understanding the genetic basis of the autolysis phenomenon of pathogenic Clostridium or solvent producing Clostridium cells might provide new insights into this important species. Genes that might be involved in autolysis of Clostridium acetobutylicum, a model clostridial species, were investigated in this study. Twelve putative autolysin genes were predicted in C. acetobutylicum DSM 1731 genome through bioinformatics analysis. Of these 12 genes, gene SMB_G3117 was selected for testing the intracellular autolysin activity, growth profile, viable cell numbers, and cellular morphology. We found that overexpression of SMB_G3117 gene led to earlier ceased growth, significantly increased number of dead cells, and clear electrolucent cavities, while disruption of SMB_G3117 gene exhibited remarkably reduced intracellular autolysin activity. These results indicate that SMB_G3117 is a novel gene involved in cellular autolysis of C. acetobutylicum.
Structural basis for differential recognition of brassinolide by its receptors
Ji She, Zhifu Han, Bin Zhou, Jijie Chai
2013, 4(6): 475-482. doi: 10.1007/s13238-013-3027-8
Brassinosteroids, a group of plant steroid hormones, regulate many aspects of plant growth and development. We and other have previously solved the crystal structures of BRI1(LRR) in complex with brassinolide, the most active brassinosteroid identified thus far. Although these studies provide a structural basis for the recognition of brassinolide by its receptor BRI1, it still remains poorly understood how the hormone differentiates among its conserved receptors. Here we present the crystal structure of the BRI1 homolog BRL1 in complex with brassinolide. The structure shows that subtle differences around the brassinolide binding site can generate a striking effect on its recognition by the BRI1 family of receptors. Structural comparison of BRL1 and BRI1 in their brassinolide-bound forms reveals the molecular basis for differential binding of brassinolide to its different receptors, which can be used for more efficient design of plant growth regulators for agricultural practice. On the basis of our structural studies and others' data, we also suggest possible mechanisms for the activation of BRI1 family receptors.