Cell Discovery

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Tsuyoshi Kawabata, Tamotsu Yoshimori
Cell Discovery, Volume 6, pp 1-14; doi:10.1038/s41421-020-0166-y

Abstract:
Autophagy degrades the cytoplasmic contents engulfed by autophagosomes. Besides providing energy and building blocks during starvation via random degradation, autophagy selectively targets cytotoxic components to prevent a wide range of diseases. This preventive activity of autophagy is supported by many studies using animal models and reports identifying several mutations in autophagy-related genes that are associated with human genetic disorders, which have been published in the past decade. Here, we summarize the molecular mechanisms of autophagosome biogenesis involving the proteins responsible for these genetic disorders, demonstrating a role for autophagy in human health. These findings will help elucidate the underlying mechanisms of autophagy-related diseases and develop future medications.
Simin Xia, Xi Chen
Cell Discovery, Volume 6, pp 1-4; doi:10.1038/s41421-020-0175-x

Abstract:
Wang, C., Horby, P. W., Hayden, F. G. & Gao, G. F. A novel coronavirus outbreak of global health concern. Lancet 395, 496–496 (2020). Zhang, Y.-Z. Novel 2019 coronavirus genome. Virological. Org. Available from: http://virological.org/t/novel-2019-coronavirus-genome/319 (2020). Corman, V. M. et al. Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR. Eurosurveillance 25, 23–30 (2020). Chu, D. K. W. et al. Molecular diagnosis of a novel coronavirus (2019-nCoV) causing an outbreak of pneumonia. Clin. Chem. 4, 549–555 (2020). Huang, C., Wang, Y. & Li, X. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395, 496–496 (2020). Li, Q. et al. Early transmission dynamics in wuhan, China, of novel coronavirus-infected pneumonia. N. Engl. J. Med. 382, 1199–1207 (2020). Balmaseda, A. et al. Antibody-based assay discriminates Zika virus infection from other flaviviruses. Proc. Natl. Acad. Sci. USA 114, 8384–8389 (2017). Myhrvold, C. et al. Field-deployable viral diagnostics using CRISPR-Cas13. Science 360, 444–448 (2018). Piepenburg, O., Williams, C. H., Stemple, D. L. & Armes, N. A. DNA detection using recombination proteins. PLoS Biol. 4, 1115–1121 (2006). Zhao, Y. X., Chen, F., Li, Q., Wang, L. H. & Fan, C. H. Isothermal amplification of nucleic acids. Chem. Rev. 115, 12491–12545 (2015). Daher, R. K., Stewart, G., Boissinot, M. & Bergeron, M. G. Recombinase polymerase amplification for diagnostic applications. Clin. Chem. 62, 947–958 (2016). Obande, G. A. & Singh, K. K. B. Current and future perspectives on isothermal nucleic acid amplification technologies for diagnosing infections. Infect. Drug Resist. 13, 455–483 (2020). Download references We thank the core facilities at The HIT Center for Life Sciences of Harbin Institute of Technology (HIT) and the startup grant from HIT. X.C. conceived and designed the experiments; S.X. and X.C. participated in multiple experiments and analyzed the data; X.C. wrote the manuscript. Correspondence to Xi Chen. The authors declare that they have no conflict of interest. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Reprints and Permissions Xia, S., Chen, X. Single-copy sensitive, field-deployable, and simultaneous dual-gene detection of SARS-CoV-2 RNA via modified RT–RPA. Cell Discov 6, 37 (2020). https://doi.org/10.1038/s41421-020-0175-x Download citation Received: 01 April 2020 Accepted: 05 May 2020 Published: 28 May 2020 DOI: https://doi.org/10.1038/s41421-020-0175-x
Taki Nishimura, Sharon A. Tooze
Cell Discovery, Volume 6, pp 1-18; doi:10.1038/s41421-020-0161-3

Abstract:
Autophagosome biogenesis is a dynamic membrane event, which is executed by the sequential function of autophagy-related (ATG) proteins. Upon autophagy induction, a cup-shaped membrane structure appears in the cytoplasm, then elongates sequestering cytoplasmic materials, and finally forms a closed double membrane autophagosome. However, how this complex vesicle formation event is strictly controlled and achieved is still enigmatic. Recently, there is accumulating evidence showing that some ATG proteins have the ability to directly interact with membranes, transfer lipids between membranes and regulate lipid metabolism. A novel role for various membrane lipids in autophagosome formation is also emerging. Here, we highlight past and recent key findings on the function of ATG proteins related to autophagosome biogenesis and consider how ATG proteins control this dynamic membrane formation event to organize the autophagosome by collaborating with membrane lipids.
Niubing Zhang, Xinyun Jing, Yuanhua Liu, Minjie Chen, Xianfeng Zhu, Jing Jiang, Hongbing Wang, Xuan Li, Pei Hao
Cell Discovery, Volume 6, pp 1-12; doi:10.1038/s41421-020-0164-0

Abstract:
CRISPRs are a promising tool being explored in combating exogenous retroviral pathogens and in disabling endogenous retroviruses for organ transplantation. The Cas12a and Cas13a systems offer novel mechanisms of CRISPR actions that have not been evaluated for retrovirus interference. Particularly, a latest study revealed that the activated Cas13a provided bacterial hosts with a “passive protection” mechanism to defend against DNA phage infection by inducing cell growth arrest in infected cells, which is especially significant as it endows Cas13a, a RNA-targeting CRISPR effector, with mount defense against both RNA and DNA invaders. Here, by refitting long terminal repeat retrotransposon Tf1 as a model system, which shares common features with retrovirus regarding their replication mechanism and life cycle, we repurposed CRISPR-Cas12a and -Cas13a to interfere with Tf1 retrotransposition, and evaluated their different mechanisms of action. Cas12a exhibited strong inhibition on retrotransposition, allowing marginal Tf1 transposition that was likely the result of a lasting pool of Tf1 RNA/cDNA intermediates protected within virus-like particles. The residual activities, however, were completely eliminated with new constructs for persistent crRNA targeting. On the other hand, targeting Cas13a to Tf1 RNA intermediates significantly inhibited Tf1 retrotransposition. However, unlike in bacterial hosts, the sustained activation of Cas13a by Tf1 transcripts did not cause cell growth arrest in S. pombe, indicating that virus-activated Cas13a likely acted differently in eukaryotic cells. The study gained insight into the actions of novel CRISPR mechanisms in combating retroviral pathogens, and established system parameters for developing new strategies in treatment of retrovirus-related diseases.
Lu Guo, Xuehan Sun, Xinge Wang, Chen Liang, Haiping Jiang, Qingqin Gao, Moyu Dai, Bin Qu, Sen Fang, Yihuan Mao, et al.
Cell Discovery, Volume 6, pp 1-4; doi:10.1038/s41421-020-0174-y

Abstract:
Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The species severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat. Microbiol. 5, 536–544 (2020). Corman, V. M. et al. Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR. Eur. Surveill. 25, 2000045 (2020). Zhang, F., Abudayyeh, O. O. & Gootenberg, J. S. A protocol for detection of COVID-19 using CRISPR diagnostics. https://www.broadinstitute.org/files/publications/special/COVID-19%20detection%20(updated).pdf (2020). Metsky, H. C. et al. CRISPR-based COVID-19 surveillance using a genomically-comprehensive machine learning approach. bioRxiv. https://doi.org/10.1101/2020.02.26.967026 (2020). Lucia, C., Federico, P. B. & Alejandra, G. C. An ultrasensitive, rapid, and portable coronavirus SARS-CoV-2 sequence detection method based on CRISPR-Cas12. bioRxiv. https://doi.org/10.1101/2020.02.29.971127 (2020). Broughton, J. P. et al. CRISPR–Cas12-based detection of SARS-CoV-2. Nat. Biotechnol. https://doi.org/10.1038/s41587-020-0513-4 (2020). Teng, F. et al. CDetection: CRISPR-Cas12b-based DNA detection with sub-attomolar sensitivity and single-base specificity. Genome Biol. 20, 132 (2019). Zhang, Y. Novel 2019 coronavirus genome. http://virological.org/t/novel-2019-coronavirus-genome/319 (2020). Grant, P. R. et al. Detection of SARS coronavirus in plasma by real-time RT-PCR. N. Engl. J. Med. 349, 2468–2469 (2003). Download references We thank professor Ng Shyh-Chang from Institute of Zoology, CAS for his critical support with this study. We thank Hanxing Zhang from Institute of Microbiology, CAS for her kind help on equipment. This work was supported by the National Key Research and Development Program (2020YFA070009 to R.R.W), the Key Research Projects of the Frontier Science of the Chinese Academy of Sciences (QYZDY-SSW-SMC002 to Q.Z. and QYZDB-SSW-SMC022 to W.L.), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16030400 to W.L.). These authors contributed equally: Xuehan Sun, Xinge Wang, Chen Liang, Haiping Jiang, Qingqin Gao, Moyu Dai L.G., R.R.W., Q.Z. and W.L. conceived and designed the experiments. L.G., X.S., X.W., C.L., H.J., Q.G., M.D., B.Q., S.F., Y.M. and Y.C. participated in multiple experiments; L.G., X.W., X.S., C.L. and G.F. analyzed the data. L.G. wrote the manuscript. W.L., R.R.W., Q.Z. and L.W. provided the final approval of the manuscript. Correspondence to Ruiqi Rachel Wang or Qi Zhou or Wei Li. The authors declare that they have no conflict of interest. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Reprints and Permissions Guo, L., Sun, X., Wang, X. et al. SARS-CoV-2 detection with CRISPR diagnostics. Cell Discov 6, 34 (2020). https://doi.org/10.1038/s41421-020-0174-y Download citation Received: 10 April 2020 Accepted: 26 April 2020 Published: 19 May 2020 DOI: https://doi.org/10.1038/s41421-020-0174-y
Jinzhong Lin, Mingxia Feng, Heping Zhang, Qunxin She
Cell Discovery, Volume 6, pp 1-16; doi:10.1038/s41421-020-0160-4

Abstract:
Antiviral defense by type III CRISPR-Cas systems relies on two distinct activities of their effectors: the RNA-activated DNA cleavage and synthesis of cyclic oligoadenylate. Both activities are featured as indiscriminate nucleic acid cleavage and subjected to the spatiotemporal regulation. To yield further insights into the involved mechanisms, we reconstituted LdCsm, a lactobacilli III-A system in Escherichia coli. Upon activation by target RNA, this immune system mediates robust DNA degradation but lacks the synthesis of cyclic oligoadenylates. Mutagenesis of the Csm3 and Cas10 conserved residues revealed that Csm3 and multiple structural domains in Cas10 function in the allosteric regulation to yield an active enzyme. Target RNAs carrying various truncations in the 3ʹ anti-tag were designed and tested for their influence on DNA binding and DNA cleavage of LdCsm. Three distinct states of ternary LdCsm complexes were identified. In particular, binding of target RNAs carrying a single nucleotide in the 3ʹ anti-tag to LdCsm yielded an active LdCsm DNase regardless whether the nucleotide shows a mismatch, as in the cognate target RNA (CTR), or a match, as in the noncognate target RNA (NTR), to the 5′ tag of crRNA. In addition, further increasing the number of 3ʹ anti-tag in CTR facilitated the substrate binding and enhanced the substrate degradation whereas doing the same as in NTR gradually decreased the substrate binding and eventually shut off the DNA cleavage by the enzyme. Together, these results provide the mechanistic insights into the allosteric activation and repression of LdCsm enzymes.
Sascha Martens, Dorotea Fracchiolla
Cell Discovery, Volume 6, pp 1-11; doi:10.1038/s41421-020-0155-1

Abstract:
ATG8 family proteins are evolutionary conserved ubiquitin-like modifiers, which become attached to the headgroup of the membrane lipid phosphatidylethanolamine in a process referred to as lipidation. This reaction is carried out analogous to the conjugation of ubiquitin to its target proteins, involving the E1-like ATG7, the E2-like ATG3 and the E3-like ATG12–ATG5–ATG16 complex, which determines the site of lipidation. ATG8 lipidation is a hallmark of autophagy where these proteins are involved in autophagosome formation, the fusion of autophagosomes with lysosomes and cargo selection. However, it has become evident that ATG8 lipidation also occurs in processes that are not directly related to autophagy. Here we discuss recent insights into the targeting of ATG8 lipidation in autophagy and other pathways with special emphasis on the recruitment and activation of the E3-like complex.
Eleanna Stamatakou, Lidia Wróbel, Sandra Malmgren Hill, Claudia Puri, Sung Min Son, Motoki Fujimaki, Ye Zhu, Farah Siddiqi, Marian Fernandez-Estevez, Marco M. Manni, et al.
Cell Discovery, Volume 6, pp 1-13; doi:10.1038/s41421-020-0158-y

Abstract:
The lysosomal degradation pathway of macroautophagy (herein referred to as autophagy) plays a crucial role in cellular physiology by regulating the removal of unwanted cargoes such as protein aggregates and damaged organelles. Over the last five decades, significant progress has been made in understanding the molecular mechanisms that regulate autophagy and its roles in human physiology and diseases. These advances, together with discoveries in human genetics linking autophagy-related gene mutations to specific diseases, provide a better understanding of the mechanisms by which autophagy-dependent pathways can be potentially targeted for treating human diseases. Here, we review mutations that have been identified in genes involved in autophagy and their associations with neurodegenerative diseases.
Wen Wen, Wenru Su, Hao Tang, Wenqing Le, Xiaopeng Zhang, Yingfeng Zheng, Xiuxing Liu, Lihui Xie, Jianmin Li, Jinguo Ye, et al.
Cell Discovery, Volume 6, pp 1-18; doi:10.1038/s41421-020-0168-9

Abstract:
COVID-19, caused by SARS-CoV-2, has recently affected over 1,200,000 people and killed more than 60,000. The key immune cell subsets change and their states during the course of COVID-19 remain unclear. We sought to comprehensively characterize the transcriptional changes in peripheral blood mononuclear cells during the recovery stage of COVID-19 by single-cell RNA sequencing technique. It was found that T cells decreased remarkably, whereas monocytes increased in patients in the early recovery stage (ERS) of COVID-19. There was an increased ratio of classical CD14++ monocytes with high inflammatory gene expression as well as a greater abundance of CD14++IL1β+ monocytes in the ERS. CD4+ T cells and CD8+ T cells decreased significantly and expressed high levels of inflammatory genes in the ERS. Among the B cells, the plasma cells increased remarkably, whereas the naïve B cells decreased. Several novel B cell-receptor (BCR) changes were identified, such as IGHV3-23 and IGHV3-7, and isotypes (IGHV3-15, IGHV3-30, and IGKV3-11) previously used for virus vaccine development were confirmed. The strongest pairing frequencies, IGHV3-23-IGHJ4, indicated a monoclonal state associated with SARS-CoV-2 specificity, which had not been reported yet. Furthermore, integrated analysis predicted that IL-1β and M-CSF may be novel candidate target genes for inflammatory storm and that TNFSF13, IL-18, IL-2, and IL-4 may be beneficial for the recovery of COVID-19 patients. Our study provides the first evidence of an inflammatory immune signature in the ERS, suggesting COVID-19 patients are still vulnerable after hospital discharge. Identification of novel BCR signaling may lead to the development of vaccines and antibodies for the treatment of COVID-19.
Xi Wang, Ruiyuan Cao, Huanyu Zhang, Jia Liu, Mingyue Xu, Hengrui Hu, Yufeng Li, Lei Zhao, Wei Li, Xiulian Sun, et al.
Cell Discovery, Volume 6, pp 1-5; doi:10.1038/s41421-020-0169-8

Abstract:
Chen, N. et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 395, 507–513 (2020). Huang, C. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395, 497–506 (2020). Wang, M. et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 30, 269–271 (2020). Wang, Z., Yang, B., Li, Q., Wen, L. & Zhang, R. Clinical Features of 69 Cases with Coronavirus Disease 2019 in Wuhan, China. Clin. Infect. Dis. ciaa272 (2020). De Clercq, E. & Li, G. Approved antiviral drugs over the past 50 years. Clin. Microbiol. Rev. 29, 695–747 (2016). Gasparini, R., Amicizia, D., Lai, P. L., Bragazzi, N. L. & Panatto, D. Compounds with anti-influenza activity: present and future of strategies for the optimal treatment and management of influenza. Part I: Influenza life-cycle and currently available drugs. J. Prev. 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Download references We thank Prof. Zhenhua Zheng from Wuhan Institute of Virology for kindly providing the anti-LAMP1 rabbit polyclonal antibody; Beijing Savant Biotechnology Co., ltd for kindly providing the anti-NP monoclonal antibody; Jia Wu, Jun Liu, and Hao Tang from BSL-3 Laboratory, and Dr. Ding Gao from the Core Faculty of Wuhan Institute of Virology for their critical support; Dr. Basil Arif for scientific editing of the paper. This work was supported by grants from the National Science and Technology Major Projects for “Major New Drugs Innovation and Development” (2018ZX09711003), the National Key R&D program of China (2020YFC0841700), and the National Natural Science Foundation of China (31621061). These authors contributed equally: Xi Wang, Ruiyuan Cao, Huanyu Zhang M.W., W.Z., and Z.H. conceived and designed the experiments. X.W., R.C., H.Z., J.L., M.X., H.H., Y.L., L.Z., W.L., X.Y., Z.S., and F.D. participated in multiple experiments; M.W., Z.H., W.Z., X.W., R.C., H.Z., J.L., M.X., H.H. Y.L., and X.S. analyzed the data. M.W., R.C., and Z.H. wrote the paper. Z.H., M.W., and W.Z. provided the final approval of the paper. Correspondence to Zhihong Hu or Wu Zhong or Manli Wang. The authors declare that they have no conflict of interest. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Reprints and Permissions Wang, X., Cao, R., Zhang, H. et al. The anti-influenza virus drug, arbidol is an efficient inhibitor of SARS-CoV-2 in vitro. Cell Discov 6, 28 (2020). https://doi.org/10.1038/s41421-020-0169-8 Download citation Received: 29 March 2020 Accepted: 11 April 2020 Published: 02 May 2020 DOI: https://doi.org/10.1038/s41421-020-0169-8
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