Article
Biochemistry & Molecular Biology
Yechun Hong, Yang Gao, Jia Pang, Huazhong Shi, Tingting Li, Huiying Meng, Dali Kong, Yunjuan Chen, Jian-Kang Zhu, Zhen Wang
Summary: Salt stress negatively affects crop production. Previous studies have implicated several spliceosome components in regulating salt stress responses in plants, but the molecular basis is not fully understood. This study shows that the spliceosomal core protein SmEb is essential for salt tolerance in Arabidopsis. Transcriptome analysis reveals that SmEb modulates alternative splicing of hundreds of pre-mRNAs in response to salt stress. Further investigation demonstrates the crucial role of SmEb in maintaining the proper ratio of two RCD1 splicing variants important for salt stress response. Moreover, RCD1.1, but not RCD1.2, interacts with stress regulators and attenuates salt sensitivity in the smeb-1 mutant by reducing salt-induced cell death. Overall, our findings highlight the essential role of SmEb in regulating alternative pre-mRNA splicing in salt stress response.
JOURNAL OF INTEGRATIVE PLANT BIOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Sierra L. L. Love, Joseph D. D. Emerson, Kazunori Koide, Aaron A. A. Hoskins
Summary: Pre-mRNA splicing is a crucial step in human gene expression, carried out by a macromolecular machine known as the spliceosome. Mutations in this machinery can lead to various human diseases. This review provides an overview of the main features of the pre-mRNA splicing machinery in humans and how changes in its components' function can result in diseases ranging from blindness to cancers. The article also discusses drugs that interact with the spliceosome to alter splicing outcomes and speculates on future treatments for spliceosomopathies.
Article
Biochemistry & Molecular Biology
Clarisse van der Feltz, Brandon Nikolai, Charles Schneider, Joshua C. Paulson, Xingyang Fu, Aaron A. Hoskins
Summary: Spliceosome catalysis is influenced by nonessential components, with Ecm2 playing a role in stabilizing catalytic sites and promoting alternate splice site usage. The interaction between Cwc2 and Ecm2 can fine-tune the spliceosome active site in unique ways, allowing for regulation of splicing of pre-mRNAs containing weak or alternate splice sites.
Review
Biochemistry & Molecular Biology
Jingya Lin, Ziqiang Zhu
Summary: This review discusses how plants adapt to high temperatures through pre-mRNA splicing, and the significance of this splicing regulation for plant growth and development.
PLANT MOLECULAR BIOLOGY
(2021)
Review
Immunology
Frank Fang Yao Lee, Scott Alper
Summary: While TLR signaling is necessary to combat infection, persistent inflammation can cause damage and contribute to various inflammatory disorders. Alternative pre-mRNA splicing plays a role in terminating TLR signaling by producing dominant negative inhibitors that limit inflammation. Understanding the production and function of these alternative isoforms may provide insights into inflammatory disease.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Multidisciplinary Sciences
Zhenwei Zhang, Norbert Rigo, Olexandr Dybkov, Jean-Baptiste Fourmann, Cindy L. Will, Vinay Kumar, Henning Urlaub, Holger Stark, Reinhard Luehrmann
Summary: During the splicing process, the integration of U2 small nuclear ribonucleoprotein into the spliceosomal A complex is facilitated by the DEAD-box helicase Prp5. Research reveals that the RNA duplex formed by U2 small nuclear RNA is proofread by Prp5, and the U2-BS helix is formed in the pre-A complex. The study further shows a large-scale remodelling of U1 and U2 snRNPs and how the binding of Hsh155(HEAT) triggers closure, disrupting Prp5 binding.
Review
Chemistry, Multidisciplinary
Jure Borisek, Lorenzo Casalino, Andrea Saltalamacchia, Suzanne G. Mays, Luca Malcovati, Alessandra Magistrato
Summary: Pre-mRNA splicing, essential for gene expression, is carried out by the spliceosome, a complex molecular machinery responsible for accurately excising intronic sequences to produce mature mRNA. The spliceosome undergoes continuous compositional and conformational remodeling to ensure splicing fidelity. Recent advances in cryo-EM have provided near-atomic resolution structures of the spliceosome, shedding light on its complexity and function. Biochemical and genetic studies, combined with biomolecular simulations, are crucial for unraveling the molecular intricacies of splicing and exploring potential therapeutic strategies for diseases associated with splicing misregulation.
ACCOUNTS OF CHEMICAL RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Kiran Kumar Kolathur, Pallavi Sharma, Nagesh Y. Y. Kadam, Navneet Shahi, Ane Nishitha, Kavita Babu, Shravan Kumar Mishra
Summary: UBL-5 is a ubiquitin-like protein that associates with proteins non-covalently and plays a conserved pre-mRNA splicing function in Caenorhabditis elegans. UBL-5 interacts with splicing factors Snu66/SART-1 and PRP-38 and other spliceosomal proteins. UBL-5 mutants in C. elegans exhibit developmental defects and splicing abnormalities for specific targets.
Review
Genetics & Heredity
Maureen V. Akinyi, Mikko J. Frilander
Summary: This article discusses the two different mechanisms for removing introns in eukaryotic species, the major spliceosome and minor spliceosome, and their interactions in shaping mRNA processing events in genes containing both major and minor introns.
FRONTIERS IN GENETICS
(2021)
Review
Plant Sciences
Wei Lan, Yuhao Qiu, Yun Xu, Yalin Liu, Ying Miao
Summary: Alternative splicing plays a critical role in plant development and response to environmental stress. Post-translational modification, such as protein ubiquitination, has been found to regulate the activity and stability of spliceosomal proteins, providing another layer of regulation for alternative splicing. This review summarizes recent studies on ubiquitin and ubiquitin-like modification of spliceosome components and discusses the relationship between spliceosome and the ubiquitin/26S proteasome pathway in plants.
FRONTIERS IN PLANT SCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Bin Guo, Xiaorui Shi, Zhe Ma, Moxuan Ji, Chu Tang, Fu Wang
Summary: A genetically engineered ratiometric dual luciferase reporter has been developed to continuously quantify changes in mRNA splice variants in vivo. This reporter system minimizes the influence of indirect factors on splicing within the same individual, with the ratio of two luciferase intensities representing the dynamic splicing efficiency of pre-mRNA. This tool offers a convenient and robust method for screening and identifying small molecules or trans-acting factors affecting specific splicing reactions.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Review
Pharmacology & Pharmacy
Maria Reviejo, Meraris Soto, Elisa Lozano, Maitane Asensio, Olga Martinez-Augustin, Fermin Sanchez de Medina, Jose J. G. Marin
Summary: Many tumors exhibit resistance to anticancer drugs, which can be intrinsic or acquired and involve multiple mechanisms. The resistance is based on the dynamic expression of over a hundred genes, forming the so-called "resistome." Splicing variants reduce the efficacy of anticancer drugs by altering molecular targets, enhancing DNA repair ability, and changing the balance between survival and apoptosis signals.
BIOCHEMICAL PHARMACOLOGY
(2021)
Review
Cell Biology
Chunbo Yang, Maria Georgiou, Robert Atkinson, Joseph Collin, Jumana Al-Aama, Sushma Nagaraja-Grellscheid, Colin Johnson, Robin Ali, Lyle Armstrong, Sina Mozaffari-Jovin, Majlinda Lako
Summary: Retinitis pigmentosa (RP) is the most common inherited retinal disease characterized by progressive photoreceptor degeneration, with mutations in PRPF genes causing dysregulation in global spliceosome function. Studies focus on key RP-PRPF genes, describing their roles in RNA splicing, impact of mutations on retinal cell function, and research in model species. Furthermore, investigations into PRPF functions beyond RNA splicing aim to provide a holistic understanding of PRPF-RP pathogenesis and develop novel therapeutic strategies.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Review
Oncology
Carlos A. Nino, Rossella Scotto di Perrotolo, Simona Polo
Summary: This review summarizes the cancer hotspot mutations in spliceosome components, focusing on the effects of mutations in U1 snRNA, SF3B1, and U2AF1 on splice site selection and cancer development.
Article
Cell Biology
Yanfei Wang, Cuiqiao Zhang, Wu Peng, Haibo Du, Yuehui Xi, Zhigang Xu
Summary: This study further explored the role of RBM24 in hearing and balance through conditional knockout mice and found that the loss of RBM24 results in severe deficits. It was observed that the development of hair cells was significantly affected, leading to degeneration and disorganization of the hair bundles. RNAseq analysis also identified several genes whose mRNA stability or pre-mRNA alternative splicing is affected by RBM24 knockout.
JOURNAL OF CELLULAR PHYSIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Guanghui Yang, Rui Zhou, Xuefei Guo, Chuangye Yan, Jianlin Lei, Yigong Shi
Summary: The development of GSIs and GSMs for Alzheimer's disease and cancer treatment presents a promising therapeutic opportunity. Cryo-electron microscopy structures reveal that these inhibitors and modulators target specific regions of gamma-secretase, interfering with substrate recruitment. Shared themes and variations in inhibitor and modulator recognition may guide the development of next-generation substrate-selective inhibitors.
Article
Multidisciplinary Sciences
Rui Bai, Ruixue Wan, Chuangye Yan, Qi Jia, Jianlin Lei, Yigong Shi
Summary: Prp2, together with its coactivator Spp2, plays a crucial role in coupling spliceosome remodeling to pre-mRNA splicing. The ATPase/helicase Prp2 loads pre-mRNA into a featured channel between the N and C halves, preventing backward sliding towards the 5'-end, and triggers unidirectional stepwise translocation towards the 3'-end through ATP binding and hydrolysis. This mechanism explains the precise regulation of spliceosome activity during pre-mRNA splicing.
Article
Multidisciplinary Sciences
Renhong Yan, Pingping Cao, Wenqi Song, Hongwu Qian, Ximing Du, Hudson W. Coates, Xin Zhao, Yaning Li, Shuai Gao, Xin Gong, Ximing Liu, Jianhua Sui, Jianlin Lei, Hongyuan Yang, Andrew J. Brown, Qiang Zhou, Chuangye Yan, Nieng Yan
Summary: The sterol regulatory element-binding protein (SREBP) pathway is controlled by membrane-embedded sterol sensors Scap, Insig-1 and Insig-2, with 25-hydroxycholesterol (25HC) serving as a master switch. Cryo-electron microscopy analysis revealed the structure of the human Scap and Insig-2 complex in the presence of 25HC, showing the critical role of 25HC binding and Insig association in regulating the pathway.
Article
Multidisciplinary Sciences
Rui Bai, Ruixue Wan, Lin Wang, Kui Xu, Qiangfeng Zhang, Jianlin Lei, Yigong Shi
Summary: The study reveals the atomic features of the activated human minor spliceosome and the proteins that stabilize its conformation, providing a framework for understanding the mechanism of the minor spliceosome function.
Letter
Cell Biology
Zeyuan Guan, Ling Yan, Qiang Wang, Liangbo Qi, Sixing Hong, Zhou Gong, Chuangye Yan, Ping Yin
Article
Multidisciplinary Sciences
Qiang Wang, Zeyuan Guan, Liangbo Qi, Jinjin Zhuang, Chen Wang, Sixing Hong, Ling Yan, Yan Wu, Xiaoqian Cao, Jianbo Cao, Junjie Yan, Tingting Zou, Zhu Liu, Delin Zhang, Chuangye Yan, Ping Yin
Summary: Sam37 stabilizes mature Tom40 mainly through electrostatic interactions, facilitating subsequent TOM assembly. These results support the b barrel switching model and offer structural insights into the assembly and release of b barrel complexes.
Article
Cell Biology
Gaoxingyu Huang, Xiechao Zhan, Chao Zeng, Xuechen Zhu, Ke Liang, Yanyu Zhao, Pan Wang, Qifan Wang, Qiang Zhou, Qinghua Tao, Minhao Liu, Jianlin Lei, Chuangye Yan, Yigong Shi
Summary: The structure of the nuclear ring subunit of the nuclear pore complex (NPC) is reported in this study. The nuclear ring subunit consists of two Y complexes, each with nucleoporin ELYS closely associated with Nup160 and Nup37. Unlike other ring subunits, the nuclear ring subunit contains only one molecule each of Nup205 and Nup93. A composite atomic model of the central ring scaffold is generated, facilitating functional understanding of vertebrate NPC.
Article
Biochemistry & Molecular Biology
Jianhua Luo, Qi Yang, Xiaofeng Zhang, Yuanyuan Zhang, Li Wan, Xiechao Zhan, Yao Zhou, Liuqing He, Danyang Li, Dazhi Jin, Ying Zhen, Jing Huang, Yanyan Li, Liang Tao
Summary: The study identified tissue factor pathway inhibitor (TFPI) as the receptor for TcdB4, a dominant virulence factor of hypervirulent clade 2 Clostridioides difficile. TFPI is highly expressed in the intestinal glands and protects the colonic epithelium from TcdB2/4. These findings reveal new mechanisms for CDI pathogenesis.
Article
Biochemistry & Molecular Biology
Xiechao Zhan, Yichen Lu, Xiaofeng Zhang, Chuangye Yan, Yigong Shi
Summary: Describes the two reactions involved in pre-mRNA splicing and presents the cryo-EM structures of intermediate spliceosomal complexes, providing insights into the molecular choreography and mechanism of exon ligation.
Article
Multidisciplinary Sciences
Xuechen Zhu, Gaoxingyu Huang, Chao Zeng, Xiechao Zhan, Ke Liang, Qikui Xu, Yanyu Zhao, Pan Wang, Qifan Wang, Qiang Zhou, Qinghua Tao, Minhao Liu, Jianlin Lei, Chuangye Yan, Yigong Shi
Summary: This study presents a cryo-electron microscopy reconstruction of the cytoplasmic ring subunit of the nuclear pore complex in Xenopus laevis. The analysis reveals the role of Nup93, Nup205, and Nup358 in facilitating and strengthening the assembly of the cytoplasmic ring scaffold.
Article
Multidisciplinary Sciences
Qiang Su, Mengying Chen, Yan Shi, Xiaofeng Zhang, Gaoxingyu Huang, Bangdong Huang, Dongwei Liu, Zhangsuo Liu, Yigong Shi
Summary: This study reports the cryo-electron microscopy structure of human IgM-BCR in the resting state and reveals the organizational principles of BCR. The findings may facilitate the design of antibody-based therapeutics.
Article
Multidisciplinary Sciences
Fenghua Yang, Tong Bian, Xiechao Zhan, Zhe Chen, Zhihan Xing, Nicolas A. A. Larsen, Xiaofeng Zhang, Yigong Shi
Summary: The authors report the high-resolution structures of two assembly precursors of human U2 snRNP and reveal that the RNA helicases DDX42 and DDX46 are mutually exclusive in terms of SF3B1-binding. The N-terminal sequences of DDX42 and DDX46 anchor on SF3B1, but their helicase domains have different interactions with U2 snRNA and TAT-SF1. Mutations in SF3B1 directly target the residues in the RNA path that interact with DDX42 and DDX46.
NATURE COMMUNICATIONS
(2023)
Article
Biology
Yini Li, Lu Tian, Ying Zhang, Yigong Shi
Summary: In Caenorhabditis elegans (C. elegans), programmed cell death is initiated by the activation of CED-3 through the assembly of the CED-4 apoptosome. Cryo-EM structures of the CED-4 apoptosome and different CED-4/CED-3 complexes reveal the distinct stages of CED-3 activation. The dynamic organization of the CED-4 apoptosome regulates the initiation of programmed cell death.
LIFE SCIENCE ALLIANCE
(2023)
Article
Cell Biology
Gaoxingyu Huang, Xiechao Zhan, Chao Zeng, Ke Liang, Xuechen Zhu, Yanyu Zhao, Pan Wang, Qifan Wang, Qiang Zhou, Qinghua Tao, Minhao Liu, Jianlin Lei, Chuangye Yan, Yigong Shi
Summary: This study presents the cryo-electron microscopy structure of the inner ring subunit from the Xenopus laevis NPC, revealing the molecular basis for the assembly of the inner ring subunit in vertebrate NPC.
