2018 Vol. 9, No. 12

Coelomocytes in C. elegans have hyperactivity of endocytosisand vacuolar dynamics. That makes worms as powerful toolsfor dissecting mechanisms of lysosome homeostasis. Li et al.performed C. elegans-based screen of natural compounds,and found a group of alkaloids that induced enlargement oflysosomes and impaired membrane integrity and lysosomalacidity dependently of STAT3 hyperactivation in both wormsand mammalian cells. Notably, these alkaloids promotedlysosomal cell death and had significant synergetic effectwith cisplatin, suggesting that lysosome-targeting naturalcompounds may have potential advantages as therapeuticapproaches for anti-tumor treatments.
Prof. Shuchün Teng: a paragon taxonomist of great passion and firm belief
Guojie Li
2018, 9(12): 983-985. doi: 10.1007/s13238-016-0348-4
Arrestins: structural disorder creates rich functionality
Vsevolod V. Gurevich, Eugenia V. Gurevich, Vladimir N. Uversky
2018, 9(12): 986-1003. doi: 10.1007/s13238-017-0501-8
Arrestins are soluble relatively small 44-46 kDa proteins that specifically bind hundreds of active phosphorylated GPCRs and dozens of non-receptor partners. There are binding partners that demonstrate preference for each of the known arrestin conformations:free, receptor-bound, and microtubule-bound. Recent evidence suggests that conformational flexibility in every functional state is the defining characteristic of arrestins. Flexibility, or plasticity, of proteins is often described as structural disorder, in contrast to the fixed conformational order observed in high-resolution crystal structures. However, protein-protein interactions often involve highly flexible elements that can assume many distinct conformations upon binding to different partners. Existing evidence suggests that arrestins are no exception to this rule:their flexibility is necessary for functional versatility. The data on arrestins and many other multi-functional proteins indicate that in many cases, "order" might be artificially imposed by highly non-physiological crystallization conditions and/or crystal packing forces. In contrast, conformational flexibility (and its extreme case, intrinsic disorder) is a more natural state of proteins, representing true biological order that underlies their physiologically relevant functions.
Transmembrane domain dependent inhibitory function of FcγRIIB
Junyi Wang, Zongyu Li, Liling Xu, Hengwen Yang, Wanli Liu
2018, 9(12): 1004-1012. doi: 10.1007/s13238-018-0509-8
FcγRIIB, the only inhibitory IgG Fc receptor, functions to suppress the hyper-activation of immune cells. Numerous studies have illustrated its inhibitory function through the ITIM motif in the cytoplasmic tail of FcγRIIB. However, later studies revealed that in addition to the ITIM, the transmembrane (TM) domain of FcγRIIB is also indispensable for its inhibitory function. Indeed, recent epidemiological studies revealed that a non-synonymous single nucleotide polymorphism (rs1050501) within the TM domain of FcγRIIB, responsible for the I232T substitution, is associated with the susceptibility to systemic lupus erythematosus (SLE). In this review, we will summarize these epidemiological and functional studies of FcγRIIB-I232T in the past few years, and will further discuss the mechanisms accounting for the functional loss of FcγRIIB-I232T. Our review will help the reader gain a deeper understanding of the importance of the TM domain in mediating the inhibitory function of FcγRIIB and may provide insights to a new therapeutic target for the associated diseases.
Research articles
C. elegans-based screen identifies lysosome-damaging alkaloids that induce STAT3-dependent lysosomal cell death
Yang Li, Yu Zhang, Qiwen Gan, Meng Xu, Xiao Ding, Guihua Tang, Jingjing Liang, Kai Liu, Xuezhao Liu, Xin Wang, Lingli Guo, Zhiyang Gao, Xiaojiang Hao, Chonglin Yang
2018, 9(12): 1013-1026. doi: 10.1007/s13238-018-0520-0
Lysosomes are degradation and signaling centers within the cell, and their dysfunction impairs a wide variety of cellular processes. To understand the cellular effect of lysosome damage, we screened natural smallmolecule compounds that induce lysosomal abnormality using Caenorhabditis elegans (C. elegans) as a model system. A group of vobasinyl-ibogan type bisindole alkaloids (ervachinines A-D) were identified that caused lysosome enlargement in C. elegans macrophage-like cells. Intriguingly, these compounds triggered cell death in the germ line independently of the canonical apoptosis pathway. In mammalian cells, ervachinines A-D induced lysosomal enlargement and damage, leading to leakage of cathepsin proteases, inhibition of autophagosome degradation and necrotic cell death. Further analysis revealed that this ervachinine-induced lysosome damage and lysosomal cell death depended on STAT3 signaling, but not RIP1 or RIP3 signaling. These findings suggest that lysosomedamaging compounds are promising reagents for dissecting signaling mechanisms underlying lysosome homeostasis and lysosome-related human disorders.
IL-23-induced macrophage polarization and its pathological roles in mice with imiquimod-induced psoriasis
Yuzhu Hou, Linnan Zhu, Hongling Tian, Hai-Xi Sun, Ruoyu Wang, Lianfeng Zhang, Yong Zhao
2018, 9(12): 1027-1038. doi: 10.1007/s13238-018-0505-z
Macrophages acquire distinct phenotypes during tissue stress and inflammatory responses. Macrophages are roughly categorized into two different subsets named inflammatory M1 and anti-inflammatory M2 macrophages. We herein identified a unique pathogenic macrophage subpopulation driven by IL-23 with a distinct gene expression profile including defined types of cytokines. The freshly isolated resting mouse peritoneal macrophages were stimulated with different cytokines in vitro, the expression of cytokines and chemokines were detected by microarray, real-time PCR, ELISA and multiple colors flow cytometry. Adoptive transfer of macrophages and imiquimod-induced psoriasis mice were used. In contrast to M1-and M2-polarized macrophages, IL-23-treated macrophages produce large amounts of IL-17A, IL-22 and IFN-γ. Biochemical and molecular studies showed that IL-23 induces IL-17A expression in macrophages through the signal transducer and activator of transcription 3 (STAT3)-retinoid related orphan receptor-γ T (RORγT) pathway. T-bet mediates the IFN-γ production in IL-23-treated macrophages. Importantly, IL-23-treated macrophages significantly promote the dermatitis pathogenesis in a psoriasis-like mouse model. IL-23-treated resting macrophages express a distinctive gene expression prolife compared with M1 and M2 macrophages. The identification of IL-23-induced macrophage polarization may help us to understand the contribution of macrophage subpopulation in Th17-cytokines-related pathogenesis.
Decreased activity of RCAN1.4 is a potential risk factor for congenital heart disease in a Han Chinese population
Liangping Cheng, Peiqiang Li, He Wang, Xueyan Yang, Huiming Zhou, Wufan Tao, Jie Tian, Hongyan Wang
2018, 9(12): 1039-1044. doi: 10.1007/s13238-018-0525-8
Architecture of SWI/SNF chromatin remodeling complex
Zhihui Zhang, Xuejuan Wang, Jiyu Xin, Zhenrui Ding, Sheng Liu, Qianglin Fang, Na Yang, Rui-min Xu, Gang Cai
2018, 9(12): 1045-1049. doi: 10.1007/s13238-018-0524-9
CD146: a potential therapeutic target for systemic sclerosis
Lingling Zhang, Yongting Luo, Xiao Teng, Zhenzhen Wu, Mengtao Li, Dong Xu, Qian Wang, Fei Wang, Jing Feng, Xiaofeng Zeng, Xiyun Yan
2018, 9(12): 1050-1054. doi: 10.1007/s13238-018-0531-x