Table of Contents
Aug 2019
Volume 29, Issue 8, Page 601-685
About the Cover:  
  RESEARCH HIGHLIGHTS   ORIGINAL ARTICLES   EDITORIAL
  REVIEW   LETTER TO EDITOR   CORRIGENDA
  RESEARCH HIGHLIGHTS
Amnon Altman 1 and Kok-Fai Kong 1
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For a long time, anti-CTLA-4 antibodies were believed to mediate their beneficial cancer immunotherapeutic effect (CITE), whose effectiveness and safety are limited by associated immune-related adverse effects (irAE), via blocking the interaction between CTLA-4 and its ligands, a mechanism known as checkpoint blockade. Using novel engineered antibodies, Zhang et al. challenge this paradigm in the present study, demonstrating that the irAE of anti-CTLA-4 antibodies can be uncoupled from their CITE, raising hopes for the design of a new generation of safer and more effective anti-CTLA-4 antibodies.
Ozren Stojanović 1,2 and Mirko Trajkovski 1,2,3
https://doi.org/10.1038/s41422-019-0200-5
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Pancreatic beta cells produce insulin on intricate cellular assembly line, but the extent of the gut microbiota involvement was not clear. It emerges that fragments of bacterial cell wall released by lysozyme 1 in the intestinal lumen are necessary to keep the machinery running, acting on the cytosolic peptidoglycan receptor Nod1 in the beta cells to regulate the insulin trafficking and glucose tolerance.
Jazeel F. Limzerwala1 and Jan M. van Deursen 1,2
https://doi.org/10.1038/s41422-019-0199-7
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BubR1 has been implicated in fundamental biological processes such as cell division, cancer, aging and age-related diseases, but whether this mitotic checkpoint protein acts as a kinase has remained a matter of intense debate. With a multi-pronged approach involving the use of structural biology, substrate identification, pharmacological inhibition of kinase activity, and functional assays, Huang et al. now provide compelling evidence that BubR1 has enzymatic activity.
Brandon Faubert1, Ralph J. DeBerardinis 1,2,3,4 and John D. Minna 5,6
https://doi.org/10.1038/s41422-019-0197-9
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Apoptosis-inducing factor has two roles: acting as an apoptosis effector and maintaining mitochondrial metabolism. A recent study uncouples these roles and finds that only the mitochondrial functions are required for tumorigenesis in mice.
  ORIGINAL ARTICLES
Yan Zhang1, Xuexiang Du1, Mingyue Liu1, Fei Tang1, Peng Zhang1, Chunxia Ai1, James K. Fields 2,3 , Eric J. Sundberg 2,4,Olga S. Latinovic 2,4, Martin Devenport5 , Pan Zheng 1,5,6 and Yang Liu 1,5,6
https://doi.org/10.1038/s41422-019-0184-1
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It remains unclear why the clinically used anti-CTLA-4 antibodies, popularly called checkpoint inhibitors, have severe immunotherapy-related adverse effects (irAEs) and yet suboptimal cancer immunotherapeutic effects (CITE). Here we report that while irAE-prone Ipilimumab and TremeIgG1 rapidly direct cell surface CTLA-4 for lysosomal degradation, the non-irAE-prone antibodies we generated, HL12 or HL32, dissociate from CTLA-4 after endocytosis and allow CTLA-4 recycling to cell surface by the LRBA-dependent mechanism. Disrupting CTLA-4 recycling results in robust CTLA-4 downregulation by all anti-CTLA-4 antibodies and confers toxicity to a non-irAE-prone anti-CTLA-4 mAb. Conversely, increasing the pH sensitivity of TremeIgG1 by introducing designed tyrosine-to-histidine mutations prevents antibody-triggered lysosomal CTLA-4 downregulation and dramatically attenuates irAE. Surprisingly, by avoiding CTLA-4 downregulation and due to their increased bioavailability, pH-sensitive anti-CTLA-4 antibodies are more effective in intratumor regulatory T-cell depletion and rejection of large established tumors. Our data establish a new paradigm for cancer research that allows for abrogating irAE while increasing CITE of anti-CTLA-4 antibodies.
Jlenia Guarnerio 1,8, Yang Zhang1, Giulia Cheloni1, Riccardo Panella1, Jesse Mae Katon1, Mark Simpson2, Akinobu Matsumoto1,Antonella Papa 1, Cristian Loretelli1, Andreas Petri3, Sakari Kauppinen3, Cassandra Garbutt4, Gunnlaugur Petur Nielsen5,Vikram Deshpande5, Mireia Castillo-Martin6, Carlos Cordon-Cardo6, Spentzos Dimitrios4, John G. Clohessy 1, Mona Batish 2,7 and Pier Paolo Pandolfi 1
https://doi.org/10.1038/s41422-019-0192-1
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circRNAs arise from back splicing events during mRNA processing, and when deregulated can play an active role in cancer. Here we characterize a new circRNA (circPOK) encoded by the Zbtb7a gene (also kown as POKEMON, LRF) in the context of mesenchymal tumor progression. circPOK functions as a non-coding proto-oncogenic RNA independently and antithetically to its linear transcript counterpart, which acts as a tumor suppressor by encoding the Pokemon transcription factor. We find that circPOK regulates pro-proliferative and pro-angiogenic factors by co-activation of the ILF2/3 complex. Importantly, the expression of Pokemon protein and circRNA is aberrantly uncoupled in cancer through differential post-transcriptional regulation. Thus, we identify a novel type of genetic unit, the iRegulon, that yields biochemically distinct RNA products, circular and linear, with diverse and antithetical functions. Our findings further expand the cellular repertoire towards the control of normal biological outputs, while aberrant expression of such components may underlie disease pathogenesis including cancer.
Yumei Zhou1, Mengxuan Li2, Yiquan Xue2, Zhiqing Li2, Weitao Wen1, Xingguang Liu2, Yuanwu Ma3, Lianfeng Zhang3, Zhongyang Shen4 and Xuetao Cao 1,2,5,6
https://doi.org/10.1038/s41422-019-0193-0
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Type I interferon (IFN-I) production is efficiently induced to ensure a potent innate immune response to viral infection. How this response can be enhanced, however, remains to be explored. Here, we identify a new cytoplasmic long non-coding RNA (lncRNA), lncLrrc55-AS, that drives a positive feedback loop to promote interferon regulatory factor 3 (IRF3) signaling and IFN-I production. We show that lncLrrc55-AS is virus-induced in multiple cell types via the IFN-JAK-STAT pathway. LncLrrc55-AS-deficient mice display a weakened antiviral immune response and are more susceptible to viral challenge. Mechanistically, lncLrrc55-AS binds phosphatase methylesterase 1 (PME-1), and promotes the interaction between PME-1 and the phosphatase PP2A, an inhibitor of IRF3 signaling. LncLrrc55-AS supports PME-1-mediated demethylation and inactivation of PP2A, thereby enhancing IRF3 phosphorylation and signaling. Loss of PME-1 phenocopies lncLrrc55-AS deficiency, leading to diminished IRF3 phosphorylation and IFN-I production. We have identified an IFN-induced lncRNA as a positive regulator of IFN-I production, adding mechanistic insight into lncRNA-mediated regulation of signaling in innate immunity and inflammation.
Jiyu Xin1, Zhu Xu1, Xuejuan Wang 1,2, Yanhua Tian3, Zhihui Zhang1 and Gang Cai 1,2
https://doi.org/10.1038/s41422-019-0176-1
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ATM/Tel1 is an apical kinase that orchestrates the multifaceted DNA damage response. Mutations of ATM/Tel1 are associated with ataxia telangiectasia syndrome. Here, we report cryo-EM structures of symmetric dimer (4.1 Å) and asymmetric dimer (4.3 Å) of Saccharomyces cerevisiae Tel1. In the symmetric state, the side chains in Tel1 C-terminus (residues 1129–2787) are discernible and an atomic model is built. The substrate binding groove is completely embedded in the symmetric dimer by the intramolecular PRD and intermolecular LID domains. Point mutations in these domains sensitize the S. cerevisiae cells to DNA damage agents and hinder Tel1 activation due to reduced binding affinity for its activator Xrs2/Nbs1. In the asymmetric state, one monomer becomes more compact in two ways: the kinase N-lobe moves down and the Spiral of α-solenoid moves upwards, which resemble the conformational changes observed in active mTOR. The accessibility of the activation loop correlates with the synergistic conformational disorders in the TRD1-TRD2 linker, FATC and PRD domains, where critical post-translational modifications and activating mutations are coincidently condensed. This study reveals a tunable allosteric network in ATM/Tel1, which is important for substrate recognition, recruitment and efficient phosphorylation.
Huijuan Yu 1,2 , Fengrui Yang 1,3, Peng Dong4, Shanhui Liao1, Wei R. Liu 1,2 , Gangyin Zhao 1,2 , Bo Qin 1,2 , Zhen Dou 2,3 , Zhe Liu4, Wei Liu5,Jianye Zang 1,3 , Jennifer Lippincott-Schwartz4, Xing Liu 1,2,3 and Xuebiao Yao 1,2,3
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Oriented cell divisions are controlled by a conserved molecular cascade involving Gαi, LGN, and NuMA. Here, we show that NDP52 regulates spindle orientation via remodeling the polar cortical actin cytoskeleton. siRNA-mediated NDP52 suppression surprisingly revealed a ring-like compact subcortical F-actin architecture surrounding the spindle in prophase/prometaphase cells, which resulted in severe defects of astral microtubule growth and an aberrant spindle orientation. Remarkably, NDP52 recruited the actin assembly factor N-WASP and regulated the dynamics of the subcortical F-actin ring in mitotic cells. Mechanistically, NDP52 was found to bind to phosphatidic acid-containing vesicles, which absorbed cytoplasmic N-WASP to regulate local filamentous actin growth at the polar cortex. Our TIRFM analyses revealed that NDP52-containing vesicles anchored N-WASP and shortened the length of actin filaments in vitro. Based on these results we propose that NDP52-containing vesicles regulate cortical actin dynamics through N-WASP to accomplish a spatiotemporal regulation between astral microtubules and the actin network for proper spindle orientation and precise chromosome segregation. In this way, intracellular vesicles cooperate with microtubules and actin filaments to regulate proper mitotic progression. Since NDP52 is absent from yeast, we reason that metazoans have evolved an elaborate spindle positioning machinery to ensure accurate chromosome segregation in mitosis.
  LETTERS TO THE EDITOR
Xueli Liu1, Jianwei Zeng1, Kai Huang1 and Jiawei Wang1
https://doi.org/10.1038/s41422-019-0194-z
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Dear Editor,

The bacterial phosphoenolpyruvate (PEP): sugar phosphotransferase system (PTS) mediates the active transport and concomitant phosphorylation of carbohydrates.1 The PTS comprises two cytoplasmic phosphoryl proteins (i.e., EI and HPr) and a species-dependent variable number of sugar-specific EII complexes (including IIA, IIB, and membrane-embedded subunits IIC/IID). EI and HPr transfer phosphoryl groups from PEP to the IIA unit. IIA and IIB sequentially transfer phosphates to sugar, which is translocated by the IIC/IID unit.2 Bacterial PTSs are classified into four evolutionarily distinct (super) families: (i) glucose/fructose/lactose (GFL) superfamily, (ii) ascorbate/galactitol (AG) superfamily, (iii) mannose–fructose–sorbose family (man-PTS), and (iv) nontransporting dihydroxyacetone family. The crystal structures of IIC transporters from GFL and AG superfamilies have been reported previously.3,4 All IIC proteins from GFL and AG superfamilies are homodimers and use an elevator mechanism to transport substrates across the cell membrane. However, the mannose family is unique in several aspects among the PTS families.1 The mannose family is the only PTS family whose members possess a IID protein, and its IIC and IID subunits have evolved in parallel and are unstable when expressed separately.2 The mannose family is also the only member among the PTS families in which the IIB constituent is phosphorylated on a histidine residue rather than a cysteine residue.3 In addition to its function in carbohydrate uptake and phosphorylation, the membrane-located components of the man-PTS complex exhibit two additional apparently unrelated activities: they play a role in the infection of Escherichia coli by bacteriophage λ for DNA penetration in the inner membrane, and they serve as target receptors for class IIa, IId, and IIe bacteriocins. Notably, class IIa and IId bacteriocins have attracted attention as potent narrow-spectrum alternatives to antibiotics or as food preservatives.5 In this study, we report the cryo-EM structure of E. coli man-PTS at resolution of 3.52 Å, which comprises ManY and ManZ, corresponding to IICMan and IIDMan components, respectively (Supplementary information, Fig. S1 and Table S1). The high quality of the ManYZ EM density allowed us to perform de novo model building for ManY and ManZ (Supplementary information, Fig. S2).6
Jianxiong Xiao 1,2, Mengjie Liu 1,2, Yilun Qi1, Yuriy Chaban3,Chao Gao1, Beiqing Pan1, Yuan Tian1, Zishuo Yu1, Jie Li4,Peijun Zhang 3,5 and Yanhui Xu 1,2,6,7
https://doi.org/10.1038/s41422-019-0205-0
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Dear Editor,

ATM (ataxia telangiectasia-mutated) is a master regulator in response to DNA damage and activates downstream pathways involved in cell cycle checkpoints, DNA damage repair, transcription regulation, immune response, central nervous system development and metabolism.1,2 Loss of ATM activity in human results in the pleiotropic neurodegeneration disorder ataxia-telangiectasia (A-T) that is characterized by immunodeficiency, cancer predisposition, premature aging and insulin-resistant diabetes.3,4,5 Despite extensive studies over the past two decades,6,7 it remains controversial how ATM is activated. Particularly, whether ATM exists in a monomeric form, whether the monomer is more active than dimer, and how dimer-to-monomer transition affects the ATM kinase activity, remain controversial.
 

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