2018 Vol. 9, No. 7

A widely used ER marker Sec61β was found to bundle
microtubules when commonly attached fluorescent protein
tag was stripped. The striking swirl-like ER morphology
is seen when the microtubule associating ER protein is
overexpressed. Here, COS-7 cells transfected with Sec61β-
HA were immunostained for HA (green) and endogenous
tubulin (red), and visualized by fluorescent confocal
microscopy. Depletion of Sec61β causes mild ER stress,
suggesting that a stable linkage between microtubule and
translocating Sec61 complex is critical for ER homeostasis.

Zhongxian Lin: Founder of color psychology in China
Hai-Feng Li, Xiao-Mei Li, Bu-Xin Han
2018, 9(7): 593-595. doi: 10.1007/s13238-017-0420-8
The development of HIV vaccines targeting gp41 membrane-proximal external region (MPER): challenges and prospects
Huan Liu, Xiaojie Su, Lulu Si, Lu Lu, Shibo Jiang
2018, 9(7): 596-615. doi: 10.1007/s13238-018-0534-7
A human immunodeficiency virus type-1 (HIV-1) vaccine which is able to effectively prevent infection would be the most powerful method of extinguishing pandemic of the acquired immunodeficiency syndrome (AIDS). Yet, achieving such vaccine remains great challenges. The membrane-proximal external region (MPER) is a highly conserved region of the envelope glycoprotein (Env) gp41 subunit near the viral envelope surface, and it plays a key role in membrane fusion. It is also the target of some reported broadly neutralizing antibodies (bNAbs). Thus, MPER is deemed to be one of the most attractive vaccine targets. However, no one can induce these bNAbs by immunization with immunogens containing the MPER sequence(s). The few attempts at developing a vaccine have only resulted in the induction of neutralizing antibodies with quite low potency and limited breadth. Thus far, vaccine failure can be attributed to various characteristics of MPER, such as those involving structure and immunology; therefore, we will focus on these and review the recent progress in the field from the following perspectives:(1) MPER structure and its role in membrane fusion, (2) the epitopes and neutralization mechanisms of MPER-specific bNAbs, as well as the limitations in eliciting neutralizing antibodies, and (3) different strategies for MPER vaccine design and current harvests.
Research articles
Sec61β facilitates the maintenance of endoplasmic reticulum homeostasis by associating microtubules
Yimeng Zhu, Gangming Zhang, Shaoyu Lin, Juanming Shi, Hong Zhang, Junjie Hu
2018, 9(7): 616-628. doi: 10.1007/s13238-017-0492-5
Sec61β, a subunit of the Sec61 translocon complex, is not essential in yeast and commonly used as a marker of endoplasmic reticulum (ER). In higher eukaryotes, such as Drosophila, deletion of Sec61β causes lethality, but its physiological role is unclear. Here, we show that Sec61β interacts directly with microtubules. Overexpression of Sec61β containing small epitope tags, but not a RFP tag, induces dramatic bundling of the ER and microtubule. A basic region in the cytosolic domain of Sec61β is critical for microtubule association. Depletion of Sec61β induces ER stress in both mammalian cells and Caenorhabditis elegans, and subsequent restoration of ER homeostasis correlates with the microtubule binding ability of Sec61β. Loss of Sec61β causes increased mobility of translocon complexes and reduced level of membrane-bound ribosomes. These results suggest that Sec61β may stabilize protein translocation by linking translocon complex to microtubule and provide insight into the physiological function of ER-microtubule interaction.
A binding-block ion selective mechanism revealed by a Na/K selective channel
Jie Yu, Bing Zhang, Yixiao Zhang, Cong-qiao Xu, Wei Zhuo, Jingpeng Ge, Jun Li, Ning Gao, Yang Li, Maojun Yang
2018, 9(7): 629-639. doi: 10.1007/s13238-017-0465-8
Mechanosensitive (MS) channels are extensively studied membrane protein for maintaining intracellular homeostasis through translocating solutes and ions across the membrane, but its mechanisms of channel gating and ion selectivity are largely unknown. Here, we identified the YnaI channel as the Na+/K+ cation-selective MS channel and solved its structure at 3.8 Å by cryoEM single-particle method. YnaI exhibits low conductance among the family of MS channels in E. coli, and shares a similar overall heptamer structure fold with previously studied MscS channels. By combining structural based mutagenesis, quantum mechanical and electrophysiological characterizations, we revealed that ion selective filter formed by seven hydrophobic methionine (YnaIMet158) in the transmembrane pore determined ion selectivity, and both ion selectivity and gating of YnaI channel were affected by accompanying anions in solution. Further quantum simulation and functional validation support that the distinct binding energies with various anions to YnaIMet158 facilitate Na+/K+ pass through, which was defined as bindingblock mechanism. Our structural and functional studies provided a new perspective for understanding the mechanism of how MS channels select ions driven by mechanical force.
Inhibition of retroviral Gag assembly by non-silencing miRNAs promotes autophagic viral degradation
Na Qu, Zhao Ma, Mengrao Zhang, Muaz N. Rushdi, Christopher J. Krueger, Antony K. Chen
2018, 9(7): 640-651. doi: 10.1007/s13238-017-0461-z
We recently reported an unconventional mechanism by which miRNAs inhibit HIV-1 viral production. This occurs when miRNAs bind nonspecifically to the viral structural protein Gag, interfering with viral RNA-mediated Gag assembly at the plasma membrane. Consequently, misassembled viral complexes are redirected into the endocytic pathway where they are delivered to lysosomes for degradation. In this study, we demonstrate that autophagy is a critical mediator of the viral degradation pathway and that this pathway is not HIV-1 specific. Misassembled viral complexes were found to colocalize extensively with LC3 and p62 in late endosomes/lysosomes, demonstrating a convergence of autophagy with functional degradative compartments. Knocking down autophagosome formation machineries reduced this convergence, while treatment with autophagy-inducer rapamycin enhanced the convergence. Furthermore, similar autophagy-dependent nonspecific miRNA inhibition of murine leukemia virus (MLV) assembly was shown. Overall, these results reveal autophagy as a crucial regulator of the retroviral degradation pathway in host cells initiated by nonspecific miRNA-Gag interactions. These findings could have significant implications for understanding how cells may regulate retroviral complex assembly by miRNA expression and autophagy, and raise the possibility that similar regulations can occur in other biological contexts.
Histone chaperone Spt16p is required for heterochromatin mediated silencing in budding yeast
Xiaowei Yan, Jiayi Yang, Jiawei Xu, Jianxun Feng, Qing Li
2018, 9(7): 652-658. doi: 10.1007/s13238-017-0485-4
Protein crystal quality oriented disulfide bond engineering
Mengchen Pu, Zhijie Xu, Yao Peng, Yaguang Hou, Dongsheng Liu, Yang Wang, Haiguang Liu, Gaojie Song, Zhi-Jie Liu
2018, 9(7): 659-663. doi: 10.1007/s13238-017-0482-7
Redirecting T cells to glypican-3 with 28.41BB.ζ and 28.ζ-41BBL CARs for hepatocellular carcinoma treatment
Haili Ma, Siye Chen, Yan He, Jingwei Huang, Yanhong Xu, Chao Wang, Cheng Lei, Ting Lu, Shengdong Xiao, Jinming Mao, Yiyun Xu, Hao Guo, Bohua Li, Minghui Zhang, Xiaowen He
2018, 9(7): 664-669. doi: 10.1007/s13238-017-0489-0