Pub Date : 2024-10-01DOI: 10.1016/j.tibs.2024.06.011
Neuronal ubiquitin balance impacts the fate of countless cellular proteins, and its disruption is associated with various neurological disorders. The ubiquitin system is critical for proper neuronal cell state transitions and the clearance of misfolded or aggregated proteins that threaten cellular integrity. This article reviews the state of and recent advancements in our understanding of the disruptions to components of the ubiquitin system, in particular E3 ligases and deubiquitylases, in neurodevelopmental and neurodegenerative diseases. Specific focus is on enzymes with recent progress in their characterization, including identifying enzyme-substrate pairs, the use of stem cell and animal models, and the development of therapeutics for ubiquitin-related diseases.
{"title":"Ubiquitin system mutations in neurological diseases","authors":"","doi":"10.1016/j.tibs.2024.06.011","DOIUrl":"10.1016/j.tibs.2024.06.011","url":null,"abstract":"<div><div>Neuronal ubiquitin balance impacts the fate of countless cellular proteins, and its disruption is associated with various neurological disorders. The ubiquitin system is critical for proper neuronal cell state transitions and the clearance of misfolded or aggregated proteins that threaten cellular integrity. This article reviews the state of and recent advancements in our understanding of the disruptions to components of the ubiquitin system, in particular E3 ligases and deubiquitylases, in neurodevelopmental and neurodegenerative diseases. Specific focus is on enzymes with recent progress in their characterization, including identifying enzyme-substrate pairs, the use of stem cell and animal models, and the development of therapeutics for ubiquitin-related diseases.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"49 10","pages":"Pages 875-887"},"PeriodicalIF":11.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141553923","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}
Pub Date : 2024-10-01DOI: 10.1016/j.tibs.2024.06.013
Jingwen Liu , Falong Lu
The poly(A) tail is an essential structural component of mRNA required for the latter’s stability and translation. Recent technologies have enabled transcriptome-wide profiling of the length and composition of poly(A) tails, shedding light on their overlooked regulatory capacities. Notably, poly(A) tails contain not only adenine but also uracil, cytosine, and guanine residues. These findings strongly suggest that poly(A) tails could encode a wealth of regulatory information, similar to known reversible RNA chemical modifications. This review aims to succinctly summarize our current knowledge on the composition, dynamics, and regulatory functions of RNA poly(A) tails. Given their capacity to carry rich regulatory information beyond the genetic code, we propose the concept of ‘poly(A) tail epigenetic information’ as a new layer of RNA epigenetic regulation.
{"title":"Beyond simple tails: poly(A) tail-mediated RNA epigenetic regulation","authors":"Jingwen Liu , Falong Lu","doi":"10.1016/j.tibs.2024.06.013","DOIUrl":"10.1016/j.tibs.2024.06.013","url":null,"abstract":"<div><div>The poly(A) tail is an essential structural component of mRNA required for the latter’s stability and translation. Recent technologies have enabled transcriptome-wide profiling of the length and composition of poly(A) tails, shedding light on their overlooked regulatory capacities. Notably, poly(A) tails contain not only adenine but also uracil, cytosine, and guanine residues. These findings strongly suggest that poly(A) tails could encode a wealth of regulatory information, similar to known reversible RNA chemical modifications. This review aims to succinctly summarize our current knowledge on the composition, dynamics, and regulatory functions of RNA poly(A) tails. Given their capacity to carry rich regulatory information beyond the genetic code, we propose the concept of ‘poly(A) tail epigenetic information’ as a new layer of RNA epigenetic regulation.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"49 10","pages":"Pages 846-858"},"PeriodicalIF":11.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141615512","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}
Pub Date : 2024-10-01DOI: 10.1016/j.tibs.2024.07.005
Jiyoung Choi , Nisha M. Rafiq , Daehun Park
The presynaptic nerve terminal is crucial for transmitting signals to the adjacent cell. To fulfill this role, specific proteins with distinct functions are concentrated in spatially confined areas within the nerve terminals. A recent concept termed liquid–liquid phase separation (LLPS) has provided new insights into how this process may occur. In this review, we aim to summarize the LLPS of proteins in different parts of the presynaptic nerve terminals, including synaptic vesicle (SV) clusters, the active zone (AZ), and the endocytic zone, with an additional focus on neurodegenerative diseases (NDDs), where the functional relevance of these properties is explored. Last, we propose new perspectives and future directions for the role of LLPS in presynaptic nerve terminals.
{"title":"Liquid–liquid phase separation in presynaptic nerve terminals","authors":"Jiyoung Choi , Nisha M. Rafiq , Daehun Park","doi":"10.1016/j.tibs.2024.07.005","DOIUrl":"10.1016/j.tibs.2024.07.005","url":null,"abstract":"<div><div>The presynaptic nerve terminal is crucial for transmitting signals to the adjacent cell. To fulfill this role, specific proteins with distinct functions are concentrated in spatially confined areas within the nerve terminals. A recent concept termed liquid–liquid phase separation (LLPS) has provided new insights into how this process may occur. In this review, we aim to summarize the LLPS of proteins in different parts of the presynaptic nerve terminals, including synaptic vesicle (SV) clusters, the active zone (AZ), and the endocytic zone, with an additional focus on neurodegenerative diseases (NDDs), where the functional relevance of these properties is explored. Last, we propose new perspectives and future directions for the role of LLPS in presynaptic nerve terminals.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"49 10","pages":"Pages 888-900"},"PeriodicalIF":11.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142091362","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}
Pub Date : 2024-10-01DOI: 10.1016/j.tibs.2024.06.006
The degradation of damaged proteins is critical for tissue integrity and organismal health because damaged proteins have a high propensity to form aggregates. E3 ubiquitin ligases are key regulators of protein quality control (PQC) and mediate the selective degradation of damaged proteins, a process termed ‘PQC degradation’ (PQCD). The degradation signals (degrons) that trigger PQCD are based on hydrophobic sites that are normally buried within the native protein structure. However, an open question is how PQCD-specialized E3 ligases distinguish between transiently misfolded proteins, which can be efficiently refolded, and permanently damaged proteins, which must be degraded. While significant progress has been made in characterizing degradation determinants, understanding the key regulatory signals of cellular and organismal PQCD pathways remains a challenge.
{"title":"UPS-dependent strategies of protein quality control degradation","authors":"","doi":"10.1016/j.tibs.2024.06.006","DOIUrl":"10.1016/j.tibs.2024.06.006","url":null,"abstract":"<div><div>The degradation of damaged proteins is critical for tissue integrity and organismal health because damaged proteins have a high propensity to form aggregates. E3 ubiquitin ligases are key regulators of protein quality control (PQC) and mediate the selective degradation of damaged proteins, a process termed ‘PQC degradation’ (PQCD). The degradation signals (degrons) that trigger PQCD are based on hydrophobic sites that are normally buried within the native protein structure. However, an open question is how PQCD-specialized E3 ligases distinguish between transiently misfolded proteins, which can be efficiently refolded, and permanently damaged proteins, which must be degraded. While significant progress has been made in characterizing degradation determinants, understanding the key regulatory signals of cellular and organismal PQCD pathways remains a challenge.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"49 10","pages":"Pages 859-874"},"PeriodicalIF":11.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141465329","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}
Pub Date : 2024-10-01DOI: 10.1016/j.tibs.2024.07.002
Andrew Savinov
Recent work from Nguyen et al. unveils massively parallel measurements of epistatic interactions between two enzymes, dihydrofolate reductase and thymidylate synthase, in their natural cellular context. Almost 3000 mutations of DHFR in three TYMS backgrounds reveal a complex interaction network. The authors capture much of this complexity using a simple model.
{"title":"Enzoology: understanding enzyme interactions and epistasis in the cell","authors":"Andrew Savinov","doi":"10.1016/j.tibs.2024.07.002","DOIUrl":"10.1016/j.tibs.2024.07.002","url":null,"abstract":"<div><div>Recent work from <span><span>Nguyen <em>et al</em>.</span><svg><path></path></svg></span><span><span><span> unveils massively parallel measurements of epistatic interactions between two enzymes, </span>dihydrofolate reductase and </span>thymidylate synthase, in their natural cellular context. Almost 3000 mutations of DHFR in three TYMS backgrounds reveal a complex interaction network. The authors capture much of this complexity using a simple model.</span></div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"49 10","pages":"Pages 841-842"},"PeriodicalIF":11.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141756458","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}
Pub Date : 2024-09-28DOI: 10.1016/j.tibs.2024.09.001
Lucía Sánchez-Alba, Helena Borràs-Gas, Ge Huang, Nathalia Varejão, David Reverter
Ubiquitin (Ub) and ubiquitin-like (UbL) modifications are critical regulators of multiple cellular processes in eukaryotes. These modifications are dynamically controlled by proteases that balance conjugation and deconjugation. In eukaryotes, these proteases include deubiquitinases (DUBs), mostly belonging to the CA-clan of cysteine proteases, and ubiquitin-like proteases (ULPs), belonging to the CE-clan proteases. Intriguingly, infectious bacteria exploit the CE-clan protease fold to generate deubiquitinating activities to disarm the immune system and degradation defenses of the host during infection. In this review, we explore the substrate preferences encoded within the CE-clan proteases and the structural determinants in the protease fold behind its selectivity, in particular those from infectious bacteria and viruses. Understanding this protease family provides crucial insights into the molecular mechanisms underlying infection and transmission of pathogenic organisms.
泛素（Ub）和类泛素（UbL）修饰是真核生物多种细胞过程的关键调节因子。这些修饰受蛋白酶的动态控制，蛋白酶可平衡共轭和解共轭作用。在真核生物中，这些蛋白酶包括主要属于半胱氨酸蛋白酶 CA 族的去泛素酶（DUBs）和属于 CE 族蛋白酶的类泛素蛋白酶（ULPs）。耐人寻味的是，感染性细菌利用 CE 族蛋白酶折叠产生去泛素化活性，从而在感染期间解除宿主免疫系统和降解防御系统的武装。在这篇综述中，我们探讨了 CE 族蛋白酶编码的底物偏好以及蛋白酶折叠结构决定因素在其选择性背后的作用，特别是那些来自传染性细菌和病毒的蛋白酶。了解这一蛋白酶家族有助于深入了解病原体感染和传播的分子机制。
{"title":"Structural diversity of the CE-clan proteases in bacteria to disarm host ubiquitin defenses.","authors":"Lucía Sánchez-Alba, Helena Borràs-Gas, Ge Huang, Nathalia Varejão, David Reverter","doi":"10.1016/j.tibs.2024.09.001","DOIUrl":"https://doi.org/10.1016/j.tibs.2024.09.001","url":null,"abstract":"<p><p>Ubiquitin (Ub) and ubiquitin-like (UbL) modifications are critical regulators of multiple cellular processes in eukaryotes. These modifications are dynamically controlled by proteases that balance conjugation and deconjugation. In eukaryotes, these proteases include deubiquitinases (DUBs), mostly belonging to the CA-clan of cysteine proteases, and ubiquitin-like proteases (ULPs), belonging to the CE-clan proteases. Intriguingly, infectious bacteria exploit the CE-clan protease fold to generate deubiquitinating activities to disarm the immune system and degradation defenses of the host during infection. In this review, we explore the substrate preferences encoded within the CE-clan proteases and the structural determinants in the protease fold behind its selectivity, in particular those from infectious bacteria and viruses. Understanding this protease family provides crucial insights into the molecular mechanisms underlying infection and transmission of pathogenic organisms.</p>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":" ","pages":""},"PeriodicalIF":11.6,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142338675","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}
Pub Date : 2024-09-01DOI: 10.1016/j.tibs.2024.06.008
While the central dogma of molecular biology describes how genetic information flows, gene expression is also affected by epigenetic and epitranscriptomic processes. A recent report by Rajan et al. demonstrates how pseudouridylation of a Leishmania ribosomal rRNA affects the expression of particular proteins: an example of epitranslatomic control.
{"title":"The Leishmania ribosome: more than passive mRNA translating machinery","authors":"","doi":"10.1016/j.tibs.2024.06.008","DOIUrl":"10.1016/j.tibs.2024.06.008","url":null,"abstract":"<div><p><span><span>While the central dogma of molecular biology describes how </span>genetic<span> information flows, gene expression is also affected by epigenetic and epitranscriptomic processes. A recent report by </span></span><span><span>Rajan <em>et al</em></span><svg><path></path></svg></span><em>.</em> demonstrates how pseudouridylation of a <span><span>Leishmania</span></span><span> ribosomal rRNA affects the expression of particular proteins: an example of epitranslatomic control.</span></p></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"49 9","pages":"Pages 754-756"},"PeriodicalIF":11.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141426003","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}
Pub Date : 2024-09-01DOI: 10.1016/j.tibs.2024.06.004
Migrasomes, newly identified organelles, play crucial roles in intercellular communication, contributing to organ development and angiogenesis. These vesicles, forming on retraction fibers of migrating cells, showcase a sophisticated architecture. Recent research reveals that migrasome biogenesis is a complicated and highly regulated process. This review summarizes the mechanisms governing migrasome formation, proposing a model in which biogenesis is understood through the lens of membrane microdomain assembly. It underscores the critical interplay between biochemistry and biophysics. The biogenesis unfolds in three distinct stages: nucleation, maturation, and expansion, each characterized by unique morphological, biochemical, and biophysical features. We also explore the broader implications of migrasome research in membrane biology and outline key unanswered questions that represent important directions for future investigation.
{"title":"Migrasome biogenesis: when biochemistry meets biophysics on membranes","authors":"","doi":"10.1016/j.tibs.2024.06.004","DOIUrl":"10.1016/j.tibs.2024.06.004","url":null,"abstract":"<div><p>Migrasomes, newly identified organelles, play crucial roles in intercellular communication, contributing to organ development and angiogenesis. These vesicles, forming on retraction fibers of migrating cells, showcase a sophisticated architecture. Recent research reveals that migrasome biogenesis is a complicated and highly regulated process. This review summarizes the mechanisms governing migrasome formation, proposing a model in which biogenesis is understood through the lens of membrane microdomain assembly. It underscores the critical interplay between biochemistry and biophysics. The biogenesis unfolds in three distinct stages: nucleation, maturation, and expansion, each characterized by unique morphological, biochemical, and biophysical features. We also explore the broader implications of migrasome research in membrane biology and outline key unanswered questions that represent important directions for future investigation.</p></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"49 9","pages":"Pages 829-840"},"PeriodicalIF":11.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141465328","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}
Pub Date : 2024-09-01DOI: 10.1016/j.tibs.2024.07.001
Agnes Ulfig , Ursula Jakob
Loss of protein homeostasis (proteostasis) is a common hallmark of aging and age-associated diseases. Considered as the guardian of proteostasis, the proteostasis network (PN) acts to preserve the functionality of proteins during their lifetime. However, its activity declines with age, leading to disease manifestation. While reactive oxygen species (ROS) were traditionally considered culprits in this process, recent research challenges this view. While harmful at high concentrations, moderate ROS levels protect the cell against age-mediated onset of proteotoxicity by activating molecular chaperones, stress response pathways, and autophagy. This review explores the nuanced roles of ROS in proteostasis and discusses the most recent findings regarding the redox regulation of the PN and its potential in extending healthspan and delaying age-related pathologies.
{"title":"Cellular oxidants and the proteostasis network: balance between activation and destruction","authors":"Agnes Ulfig , Ursula Jakob","doi":"10.1016/j.tibs.2024.07.001","DOIUrl":"10.1016/j.tibs.2024.07.001","url":null,"abstract":"<div><p>Loss of protein homeostasis (proteostasis) is a common hallmark of aging and age-associated diseases. Considered as the guardian of proteostasis, the proteostasis network (PN) acts to preserve the functionality of proteins during their lifetime. However, its activity declines with age, leading to disease manifestation. While reactive oxygen species (ROS) were traditionally considered culprits in this process, recent research challenges this view. While harmful at high concentrations, moderate ROS levels protect the cell against age-mediated onset of proteotoxicity by activating molecular chaperones, stress response pathways, and autophagy. This review explores the nuanced roles of ROS in proteostasis and discusses the most recent findings regarding the redox regulation of the PN and its potential in extending healthspan and delaying age-related pathologies.</p></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"49 9","pages":"Pages 761-774"},"PeriodicalIF":11.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0968000424001646/pdfft?md5=e438983700d0e46168c3bfae96cab77d&pid=1-s2.0-S0968000424001646-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142015999","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}
Pub Date : 2024-09-01DOI: 10.1016/j.tibs.2024.07.004
Ecaterina Cozma , Patrick Penndorf
The International Union of Biochemistry and Molecular Biology (IUBMB) Trainee Initiative aims to identify challenges experienced by biochemistry and molecular biology trainees and create programming to foster their growth and development as the next generation of scientists. Here, we highlight resources and events developed by the Trainee Initiative in their endeavor to support trainees around the world.
{"title":"IUBMB Trainee Initiative: supporting emerging biochemists and molecular biologists around the world","authors":"Ecaterina Cozma , Patrick Penndorf","doi":"10.1016/j.tibs.2024.07.004","DOIUrl":"10.1016/j.tibs.2024.07.004","url":null,"abstract":"<div><p>The International Union of Biochemistry and Molecular Biology (IUBMB) Trainee Initiative aims to identify challenges experienced by biochemistry and molecular biology trainees and create programming to foster their growth and development as the next generation of scientists. Here, we highlight resources and events developed by the Trainee Initiative in their endeavor to support trainees around the world.</p></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"49 9","pages":"Pages 749-751"},"PeriodicalIF":11.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0968000424001816/pdfft?md5=1766f2b5945a5294a72bfa46625178ac&pid=1-s2.0-S0968000424001816-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142144854","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}
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