Cell Research最新文献

{"title":"Coding, or non-coding, that is the question","authors":"Laura Poliseno, Martina Lanza, Pier Paolo Pandolfi","doi":"10.1038/s41422-024-00975-8","DOIUrl":"10.1038/s41422-024-00975-8","url":null,"abstract":"The advent of high-throughput sequencing uncovered that our genome is pervasively transcribed into RNAs that are seemingly not translated into proteins. It was also found that non-coding RNA transcripts outnumber canonical protein-coding genes. This mindboggling discovery prompted a surge in non-coding RNA research that started unraveling the functional relevance of these new genetic units, shaking the classic definition of “gene”. While the non-coding RNA revolution was still taking place, polysome/ribosome profiling and mass spectrometry analyses revealed that peptides can be translated from non-canonical open reading frames. Therefore, it is becoming evident that the coding vs non-coding dichotomy is way blurrier than anticipated. In this review, we focus on several examples in which the binary classification of coding vs non-coding genes is outdated, since the same bifunctional gene expresses both coding and non-coding products. We discuss the implications of this intricate usage of transcripts in terms of molecular mechanisms of gene expression and biological outputs, which are often concordant, but can also surprisingly be discordant. Finally, we discuss the methodological caveats that are associated with the study of bifunctional genes, and we highlight the opportunities and challenges of therapeutic exploitation of this intricacy towards the development of anticancer therapies.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"34 9","pages":"609-629"},"PeriodicalIF":28.1,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41422-024-00975-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141755093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Author Correction: Discovery and structural mechanism of DNA endonucleases guided by RAGATH-18-derived RNAs","authors":"Kuan Ren, Fengxia Zhou, Fan Zhang, Mingyu Yin, Yuwei Zhu, Shouyu Wang, Yan Chen, Tengjin Huang, Zixuan Wu, Jiale He, Anqi Zhang, Changyou Guo, Zhiwei Huang","doi":"10.1038/s41422-024-00999-0","DOIUrl":"10.1038/s41422-024-00999-0","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"34 11","pages":"814-814"},"PeriodicalIF":28.1,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41422-024-00999-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141751214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rejuvenating immunity through a balancing stem cell act.","authors":"Sten Eirik W Jacobsen","doi":"10.1038/s41422-024-01005-3","DOIUrl":"https://doi.org/10.1038/s41422-024-01005-3","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":" ","pages":""},"PeriodicalIF":28.1,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141751215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deletion of V483 in the spike confers evolutionary advantage on SARS-CoV-2 for human adaptation and host-range expansion after a prolonged pandemic","authors":"Can Yue, Shuo Liu, Bo Meng, Kaiyue Fan, Sijie Yang, Pan Liu, Qianhui Zhu, Xin Mao, Yuanling Yu, Fei Shao, Peng Wang, Youchun Wang, Ravindra Kumar Gupta, Yunlong Cao, Xiangxi Wang","doi":"10.1038/s41422-024-01000-8","DOIUrl":"10.1038/s41422-024-01000-8","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"34 10","pages":"739-742"},"PeriodicalIF":28.1,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41422-024-01000-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141726114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Painful memories boost protective immunity","authors":"Tri Giang Phan, Elissa K. Deenick","doi":"10.1038/s41422-024-01002-6","DOIUrl":"10.1038/s41422-024-01002-6","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"34 11","pages":"751-752"},"PeriodicalIF":28.1,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41422-024-01002-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141723212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel insight into atrioventricular node conduction","authors":"Lu Ren, Joseph C. Wu","doi":"10.1038/s41422-024-00996-3","DOIUrl":"10.1038/s41422-024-00996-3","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"34 8","pages":"539-540"},"PeriodicalIF":28.1,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11291708/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141626193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Body–brain axis: orchestrating immune responses","authors":"Leon Hosang, Alexander Flügel, Francesca Odoardi","doi":"10.1038/s41422-024-01004-4","DOIUrl":"10.1038/s41422-024-01004-4","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"34 11","pages":"757-758"},"PeriodicalIF":28.1,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41422-024-01004-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141626192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural basis of tethered agonism and G protein coupling of protease-activated receptors","authors":"Jia Guo, Yun-Li Zhou, Yixin Yang, Shimeng Guo, Erli You, Xin Xie, Yi Jiang, Chunyou Mao, H. Eric Xu, Yan Zhang","doi":"10.1038/s41422-024-00997-2","DOIUrl":"10.1038/s41422-024-00997-2","url":null,"abstract":"Protease-activated receptors (PARs) are a unique group within the G protein-coupled receptor superfamily, orchestrating cellular responses to extracellular proteases via enzymatic cleavage, which triggers intracellular signaling pathways. Protease-activated receptor 1 (PAR1) is a key member of this family and is recognized as a critical pharmacological target for managing thrombotic disorders. In this study, we present cryo-electron microscopy structures of PAR1 in its activated state, induced by its natural tethered agonist (TA), in complex with two distinct downstream proteins, the Gq and Gi heterotrimers, respectively. The TA peptide is positioned within a surface pocket, prompting PAR1 activation through notable conformational shifts. Contrary to the typical receptor activation that involves the outward movement of transmembrane helix 6 (TM6), PAR1 activation is characterized by the simultaneous downward shift of TM6 and TM7, coupled with the rotation of a group of aromatic residues. This results in the displacement of an intracellular anion, creating space for downstream G protein binding. Our findings delineate the TA recognition pattern and highlight a distinct role of the second extracellular loop in forming β-sheets with TA within the PAR family, a feature not observed in other TA-activated receptors. Moreover, the nuanced differences in the interactions between intracellular loops 2/3 and the Gα subunit of different G proteins are crucial for determining the specificity of G protein coupling. These insights contribute to our understanding of the ligand binding and activation mechanisms of PARs, illuminating the basis for PAR1’s versatility in G protein coupling.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"34 10","pages":"725-734"},"PeriodicalIF":28.1,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41422-024-00997-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141597399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Perenniality: the tale of three MADS-box genes","authors":"Zheng Li, Ruichen Ma, Rishikesh P. Bhalerao","doi":"10.1038/s41422-024-01001-7","DOIUrl":"10.1038/s41422-024-01001-7","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"34 11","pages":"753-754"},"PeriodicalIF":28.1,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41422-024-01001-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141584240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zero-shot prediction of mutation effects with multimodal deep representation learning guides protein engineering","authors":"Peng Cheng, Cong Mao, Jin Tang, Sen Yang, Yu Cheng, Wuke Wang, Qiuxi Gu, Wei Han, Hao Chen, Sihan Li, Yaofeng Chen, Jianglin Zhou, Wuju Li, Aimin Pan, Suwen Zhao, Xingxu Huang, Shiqiang Zhu, Jun Zhang, Wenjie Shu, Shengqi Wang","doi":"10.1038/s41422-024-00989-2","DOIUrl":"10.1038/s41422-024-00989-2","url":null,"abstract":"Mutations in amino acid sequences can provoke changes in protein function. Accurate and unsupervised prediction of mutation effects is critical in biotechnology and biomedicine, but remains a fundamental challenge. To resolve this challenge, here we present Protein Mutational Effect Predictor (ProMEP), a general and multiple sequence alignment-free method that enables zero-shot prediction of mutation effects. A multimodal deep representation learning model embedded in ProMEP was developed to comprehensively learn both sequence and structure contexts from ~160 million proteins. ProMEP achieves state-of-the-art performance in mutational effect prediction and accomplishes a tremendous improvement in speed, enabling efficient and intelligent protein engineering. Specifically, ProMEP accurately forecasts mutational consequences on the gene-editing enzymes TnpB and TadA, and successfully guides the development of high-performance gene-editing tools with their engineered variants. The gene-editing efficiency of a 5-site mutant of TnpB reaches up to 74.04% (vs 24.66% for the wild type); and the base editing tool developed on the basis of a TadA 15-site mutant (in addition to the A106V/D108N double mutation that renders deoxyadenosine deaminase activity to TadA) exhibits an A-to-G conversion frequency of up to 77.27% (vs 69.80% for ABE8e, a previous TadA-based adenine base editor) with significantly reduced bystander and off-target effects compared to ABE8e. ProMEP not only showcases superior performance in predicting mutational effects on proteins but also demonstrates a great capability to guide protein engineering. Therefore, ProMEP enables efficient exploration of the gigantic protein space and facilitates practical design of proteins, thereby advancing studies in biomedicine and synthetic biology.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"34 9","pages":"630-647"},"PeriodicalIF":28.1,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41422-024-00989-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141537604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}