2018 Vol. 9, No. 6

On the cover: A snapshot of the sympathetic arborizations
in mouse inguinal white adipose tissues, immunolabeled
with anti-tyrosine hydroxylase antibody and visualized by
the 3D volume fluorescence-imaging. In this issue of Protein
& Cell, Cao et al. exploit the new volume fluorescence-
imaging technique and demonstrate the significant, and
also reversible, plasticity of intra-adipose sympathetic
arborizations in response to cold challenge. They show that
this sympathetic plasticity depends on the cold-elicited signal
of nerve growth factor and TrkA receptor, which depends
on the feedback action of catecholamine signal upon cold
challenge. They therefore reveal the key physiological
relevance, together with the regulatory mechanism, of intra-
adipose sympathetic plasticity in the white adipose tissues.
Simulating the ion permeation and ion selection for a eukaryotic voltage-gated sodium channel NaVPaS
Juanrong Zhang, Wenzhi Mao, Yanhui Ren, Rui-Ning Sun, Nieng Yan, Haipeng Gong
2018, 9(6): 580-585. doi: 10.1007/s13238-018-0522-y
UQCRFS1N assembles mitochondrial respiratory complex-Ⅲ into an asymmetric 21-subunit dimer
Shuai Zong, Jinke Gu, Tianya Liu, Runyu Guo, Meng Wu, Maojun Yang
2018, 9(6): 586-591. doi: 10.1007/s13238-018-0515-x
The symbol of spread of modern Western botany into China: Chih-wu hsüeh, an unconventional translation in the late Qing dynasty
He Zhang
2018, 9(6): 511-515. doi: 10.1007/s13238-017-0452-0
Targeting cancer stem cells by using chimeric antigen receptor-modified T cells: a potential and curable approach for cancer treatment
Yelei Guo, Kaichao Feng, Yao Wang, Weidong Han
2018, 9(6): 516-526. doi: 10.1007/s13238-017-0394-6
Cancer stem cells (CSCs), a subpopulation of tumor cells, have self-renewal and multi-lineage differentiation abilities that play an important role in cancer initiation, maintenance, and metastasis. An accumulation of evidence indicates that CSCs can cause conventional therapy failure and cancer recurrence because of their treatment resistance and self-regeneration characteristics. Therefore, approaches that specifically and efficiently eliminate CSCs to achieve a durable clinical response are urgently needed. Currently, treatments with chimeric antigen receptor-modified T (CART) cells have shown successful clinical outcomes in patients with hematologic malignancies, and their safety and feasibility in solid tumors was confirmed. In this review, we will discuss in detail the possibility that CART cells inhibit CSCs by specifically targeting their cell surface markers, which will ultimately improve the clinical response for patients with various types of cancer. A number of viewpoints were summarized to promote the application of CSC-targeted CART cells in clinical cancer treatment. This review covers the key aspects of CSC-targeted CART cells against cancers in accordance with the premise of the model, from bench to bedside and back to bench.
Research articles
Whole-tissue 3D imaging reveals intra-adipose sympathetic plasticity regulated by NGF-TrkA signal in cold-induced beiging
Ying Cao, Huanhuan Wang, Wenwen Zeng
2018, 9(6): 527-539. doi: 10.1007/s13238-018-0528-5
Sympathetic arborizations act as the essential efferent signals in regulating the metabolism of peripheral organs including white adipose tissues (WAT). However, whether these local neural structures would be of plastic nature, and how such plasticity might participate in specific metabolic events of WAT, remains largely uncharacterized. In this study, we exploit the new volume fluorescence-imaging technique to observe the significant, and also reversible, plasticity of intra-adipose sympathetic arborizations in mouse inguinal WAT in response to cold challenge. We demonstrate that this sympathetic plasticity depends on the cold-elicited signal of nerve growth factor (NGF) and TrkA receptor. Blockage of NGF or TrkA signaling suppresses intraadipose sympathetic plasticity, and moreover, the coldinduced beiging process of WAT. Furthermore, we show that NGF expression in WAT depends on the catecholamine signal in cold challenge. We therefore reveal the key physiological relevance, together with the regulatory mechanism, of intra-adipose sympathetic plasticity in the WAT metabolism.
Antisense transcription regulates the expression of sense gene via alternative polyadenylation
Ting Shen, Huan Li, Yifan Song, Jun Yao, Miao Han, Ming Yu, Gang Wei, Ting Ni
2018, 9(6): 540-552. doi: 10.1007/s13238-017-0497-0
Natural antisense transcripts (NAT) and alternative polyadenylation (APA) of messenger RNA (mRNA) are important contributors of transcriptome complexity, each playing a critical role in multiple biological processes. However, whether they have crosstalk and function collaboratively is unclear. We discovered that APA enriched in human sense-antisense (S-AS) gene pairs, and finally focused on RNASEH2C-KAT5 S-AS pair for further study. In cis but not in trans over-expression of the antisense KAT5 gene promoted the usage of distal polyA (pA) site in sense gene RNASEH2C, which generated longer 3' untranslated region (3'UTR) and produced less protein, accompanying with slowed cell growth. Mechanistically, elevated Pol Ⅱ occupancy coupled with SRSF3 could explain the higher usage of distal pA site. Finally, NAT-mediated downregulation of sense gene's protein level in RNASEH2C-KAT5 pair was specific for human rather than mouse, which lacks the distal pA site of RNASEH2C. We provided the first evidence to support that certain gene affected phenotype may not by the protein of its own, but by affecting the expression of its overlapped gene through APA, implying an unexpected view for understanding the link between genotype and phenotype.
Ligand binding and conformational changes of SUR1 subunit in pancreatic ATP-sensitive potassium channels
Jing-Xiang Wu, Dian Ding, Mengmeng Wang, Yunlu Kang, Xin Zeng, Lei Chen
2018, 9(6): 553-567. doi: 10.1007/s13238-018-0530-y
ATP-sensitive potassium channels (KATP) are energy sensors on the plasma membrane. By sensing the intracellular ADP/ATP ratio of β-cells, pancreatic KATP channels control insulin release and regulate metabolism at the whole body level. They are implicated in many metabolic disorders and diseases and are therefore important drug targets. Here, we present three structures of pancreatic KATP channels solved by cryoelectron microscopy (cryo-EM), at resolutions ranging from 4.1 to 4.5 Å. These structures depict the binding site of the antidiabetic drug glibenclamide, indicate how Kir6.2 (inward-rectifying potassium channel 6.2) N-terminus participates in the coupling between the peripheral SUR1 (sulfonylurea receptor 1) subunit and the central Kir6.2 channel, reveal the binding mode of activating nucleotides, and suggest the mechanism of how Mg-ADP binding on nucleotide binding domains (NBDs) drives a conformational change of the SUR1 subunit.
Identification of natural compounds targeting Annexin A2 with an anti-cancer effect
Yu-Shi Wang, He Li, Yang Li, Hongyan Zhu, Ying-Hua Jin
2018, 9(6): 568-579. doi: 10.1007/s13238-018-0513-z
Annexin A2, a multifunctional tumor associated protein, promotes nuclear factor-kappa B (NF-κB) activation by interacting with NF-κB p50 subunit and facilitating its nuclear translocation. Here we demonstrated that two ginsenosides Rg5 (G-Rg5) and Rk1 (G-Rk1), with similar structure, directly bound to Annexin A2 by molecular docking and cellular thermal shift assay. Both Rg5 and Rk1 inhibited the interaction between Annexin A2 and NF-κB p50 subunit, their translocation to nuclear and NF-κB activation. Inhibition of NF-κB by these two ginsenosides decreased the expression of inhibitor of apoptosis proteins (IAPs), leading to caspase activation and apoptosis. Over expression of K302A Annexin A2, a mutant version of Annexin A2, which fails to interact with G-Rg5 and G-Rk1, effectively reduced the NF-κB inhibitory effect and apoptosis induced by G-Rg5 and G-Rk1. In addition, the knockdown of Annexin A2 largely enhanced NF-κB activation and apoptosis induced by the two molecules, indicating that the effects of G-Rg5 and G-Rk1 on NF-κB were mainly mediated by Annexin A2. Taken together, this study for the first time demonstrated that G-Rg5 and G-Rk1 inhibit tumor cell growth by targeting Annexin A2 and NF-κB pathway, and G-Rg5 and G-Rk1 might be promising natural compounds for targeted cancer therapy.