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":null,"pages":null},"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.2024.07.005
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":"","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":null,"pages":null},"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.2024.06.013
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":"","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":null,"pages":null},"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.2024.06.006
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":null,"pages":null},"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
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":"","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":null,"pages":null},"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":null,"pages":null},"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 : 2024-09-12DOI: 10.1016/j.tibs.2024.08.003
Carsten Peters,Martin Haslbeck,Johannes Buchner
Small heat shock proteins (sHsps) are an important part of the cellular system maintaining protein homeostasis under physiological and stress conditions. As molecular chaperones, they form complexes with different non-native proteins in an ATP-independent manner. Many sHsps populate ensembles of energetically similar but different-sized oligomers. Regulation of chaperone activity occurs by changing the equilibrium of these ensembles. This makes sHsps a versatile and adaptive system for trapping non-native proteins in complexes, allowing recycling with the help of ATP-dependent chaperones. In this review, we discuss progress in our understanding of the structural principles of sHsp oligomers and their functional principles, as well as their roles in aging and eye lens transparency.
小热休克蛋白（sHsps）是在生理和应激条件下维持蛋白质平衡的细胞系统的重要组成部分。作为分子伴侣，它们以不依赖 ATP 的方式与不同的非本源蛋白质形成复合物。许多 sHsps 形成了能量相似但大小不同的寡聚体组合。通过改变这些组合体的平衡来调节伴侣活性。这使得 sHsps 成为一种多功能的适应性系统，可将非本地蛋白质困在复合物中，并在 ATP 依赖性伴侣的帮助下进行回收。在这篇综述中，我们将讨论对 sHsp 寡聚体结构原理及其功能原理的理解进展，以及它们在衰老和眼睛晶状体透明度中的作用。
{"title":"Catchers of folding gone awry: a tale of small heat shock proteins.","authors":"Carsten Peters,Martin Haslbeck,Johannes Buchner","doi":"10.1016/j.tibs.2024.08.003","DOIUrl":"https://doi.org/10.1016/j.tibs.2024.08.003","url":null,"abstract":"Small heat shock proteins (sHsps) are an important part of the cellular system maintaining protein homeostasis under physiological and stress conditions. As molecular chaperones, they form complexes with different non-native proteins in an ATP-independent manner. Many sHsps populate ensembles of energetically similar but different-sized oligomers. Regulation of chaperone activity occurs by changing the equilibrium of these ensembles. This makes sHsps a versatile and adaptive system for trapping non-native proteins in complexes, allowing recycling with the help of ATP-dependent chaperones. In this review, we discuss progress in our understanding of the structural principles of sHsp oligomers and their functional principles, as well as their roles in aging and eye lens transparency.","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":null,"pages":null},"PeriodicalIF":13.8,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267666","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 : 2024-09-11DOI: 10.1016/j.tibs.2024.08.004
Thibault Houles,Sang-Oh Yoon,Philippe P Roux
Protein phosphorylation is a crucial regulatory mechanism in cell signaling, acting as a molecular switch that modulates protein function. Catalyzed by protein kinases and reversed by phosphoprotein phosphatases, it is essential in both normal physiological and pathological states. Recent advances have uncovered a vast and intricate landscape of protein phosphorylation that include histidine phosphorylation and more unconventional events, such as pyrophosphorylation and polyphosphorylation. Many questions remain about the true size of the phosphoproteome and, more importantly, its site-specific functional relevance. The involvement of unconventional actors such as pseudokinases and pseudophosphatases adds further complexity to be resolved. This review explores recent discoveries and ongoing challenges, highlighting the need for continued research to fully elucidate the roles and regulation of protein phosphorylation.
{"title":"The expanding landscape of canonical and non-canonical protein phosphorylation.","authors":"Thibault Houles,Sang-Oh Yoon,Philippe P Roux","doi":"10.1016/j.tibs.2024.08.004","DOIUrl":"https://doi.org/10.1016/j.tibs.2024.08.004","url":null,"abstract":"Protein phosphorylation is a crucial regulatory mechanism in cell signaling, acting as a molecular switch that modulates protein function. Catalyzed by protein kinases and reversed by phosphoprotein phosphatases, it is essential in both normal physiological and pathological states. Recent advances have uncovered a vast and intricate landscape of protein phosphorylation that include histidine phosphorylation and more unconventional events, such as pyrophosphorylation and polyphosphorylation. Many questions remain about the true size of the phosphoproteome and, more importantly, its site-specific functional relevance. The involvement of unconventional actors such as pseudokinases and pseudophosphatases adds further complexity to be resolved. This review explores recent discoveries and ongoing challenges, highlighting the need for continued research to fully elucidate the roles and regulation of protein phosphorylation.","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":null,"pages":null},"PeriodicalIF":13.8,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267667","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":null,"pages":null},"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":null,"pages":null},"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}
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