Pub Date : 2024-11-14DOI: 10.1016/j.tcb.2024.11.002
Karen M Mann
Transposable elements (TEs) account for 50% of the human genome and have essential functions as gene promoters. A subset of TEs is expressed in normal cells and differentially expressed in cancers, yet their biological significance is understudied. In a recent article, Tu et al. describe the tumor suppressive function of POGK, an expressed TE with a KRAB domain, and its cooperation with TRIM28 to repress ribosomal gene transcription in triple-negative breast cancer (TNBC).
可转座元件(TEs)占人类基因组的 50%,具有基因启动子的基本功能。可转座元件的一个子集在正常细胞中表达,而在癌症中则有不同表达,但它们的生物学意义还未得到充分研究。在最近的一篇文章中,Tu 等人描述了具有 KRAB 结构域的表达 TE POGK 的肿瘤抑制功能,以及它与 TRIM28 合作抑制三阴性乳腺癌(TNBC)中核糖体基因转录的功能。
{"title":"POGK is a domesticated KRAB domain-containing transposable element with tumor suppressive functions in breast cancer.","authors":"Karen M Mann","doi":"10.1016/j.tcb.2024.11.002","DOIUrl":"https://doi.org/10.1016/j.tcb.2024.11.002","url":null,"abstract":"<p><p>Transposable elements (TEs) account for 50% of the human genome and have essential functions as gene promoters. A subset of TEs is expressed in normal cells and differentially expressed in cancers, yet their biological significance is understudied. In a recent article, Tu et al. describe the tumor suppressive function of POGK, an expressed TE with a KRAB domain, and its cooperation with TRIM28 to repress ribosomal gene transcription in triple-negative breast cancer (TNBC).</p>","PeriodicalId":56085,"journal":{"name":"Trends in Cell Biology","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640337","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 : 2024-11-14DOI: 10.1016/j.tcb.2024.10.003
Claudio Hetz, Andrew Dillin
Aging trajectories vary among individuals, characterized by progressive functional decline, often leading to disease states. One of the central hallmarks of aging is the deterioration of proteostasis, where the function of the endoplasmic reticulum (ER) is dramatically affected. ER stress is monitored and adjusted by the unfolded protein response (UPR); a signaling pathway that mediates adaptive processes to restore proteostasis. Studies in multiple model organisms (yeast, worms, flies, and mice) in addition to human tissue indicates that adaptive UPR signaling contributes to healthy aging. Strategies to improve ER proteostasis using small molecules and gene therapy reduce the decline of organ function during normal aging in mammals. This article reviews recent advances in understanding the significance of the ER proteostasis network to normal aging and its relationship with other hallmarks of aging such as senescence.
衰老的轨迹因人而异,其特点是功能逐渐衰退,往往导致疾病状态。衰老的核心特征之一是蛋白稳态恶化,内质网(ER)的功能受到严重影响。未折叠蛋白反应(UPR)可监测和调节 ER 压力;UPR 是一种信号通路,可介导恢复蛋白稳态的适应过程。对多种模式生物(酵母、蠕虫、苍蝇和小鼠)以及人体组织的研究表明,适应性 UPR 信号传导有助于健康老化。利用小分子和基因疗法改善ER蛋白稳态的策略可减少哺乳动物正常衰老过程中器官功能的衰退。本文回顾了在理解ER蛋白稳态网络对正常衰老的意义及其与衰老的其他标志(如衰老)之间的关系方面的最新进展。
{"title":"Central role of the ER proteostasis network in healthy aging.","authors":"Claudio Hetz, Andrew Dillin","doi":"10.1016/j.tcb.2024.10.003","DOIUrl":"https://doi.org/10.1016/j.tcb.2024.10.003","url":null,"abstract":"<p><p>Aging trajectories vary among individuals, characterized by progressive functional decline, often leading to disease states. One of the central hallmarks of aging is the deterioration of proteostasis, where the function of the endoplasmic reticulum (ER) is dramatically affected. ER stress is monitored and adjusted by the unfolded protein response (UPR); a signaling pathway that mediates adaptive processes to restore proteostasis. Studies in multiple model organisms (yeast, worms, flies, and mice) in addition to human tissue indicates that adaptive UPR signaling contributes to healthy aging. Strategies to improve ER proteostasis using small molecules and gene therapy reduce the decline of organ function during normal aging in mammals. This article reviews recent advances in understanding the significance of the ER proteostasis network to normal aging and its relationship with other hallmarks of aging such as senescence.</p>","PeriodicalId":56085,"journal":{"name":"Trends in Cell Biology","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640336","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 : 2024-11-14DOI: 10.1016/j.tcb.2024.10.011
Yaping Meng, Xinran Li, Haoxing Xu
The cGAS-STING pathway senses the level of double-stranded (ds)DNA in the cytosol, and is required for innate immunity through its effector, TBK1. A recent study by Lv et al. reports that STING activation also simultaneously promotes lysosomal biogenesis by inducing nuclear translocation of the transcription factors TFEB/TFE3 independent of TBK1.
{"title":"TFEB links the cGAS-STING pathway to lysosome biogenesis.","authors":"Yaping Meng, Xinran Li, Haoxing Xu","doi":"10.1016/j.tcb.2024.10.011","DOIUrl":"https://doi.org/10.1016/j.tcb.2024.10.011","url":null,"abstract":"<p><p>The cGAS-STING pathway senses the level of double-stranded (ds)DNA in the cytosol, and is required for innate immunity through its effector, TBK1. A recent study by Lv et al. reports that STING activation also simultaneously promotes lysosomal biogenesis by inducing nuclear translocation of the transcription factors TFEB/TFE3 independent of TBK1.</p>","PeriodicalId":56085,"journal":{"name":"Trends in Cell Biology","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640338","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 : 2024-11-09DOI: 10.1016/j.tcb.2024.10.004
Can Pan, Xueping Wang, Chuan Yang, Kai Fu, Fang Wang, Liwu Fu
Circulating tumor cells (CTCs), which have the heterogeneity and histological properties of the primary tumor and metastases, are shed from the primary tumor and/or metastatic lesions into the vasculature and initiate metastases at remote sites. In the clinic, CTCs are used extensively in liquid biopsies for early screening, diagnosis, treatment, and prognosis. Current research focuses on using CTC-derived models to study tumor heterogeneity and metastasis, with 3D organoids emerging as a promising tool in cancer research and precision oncology. However, isolating and enriching CTCs from blood remains challenging due to their scarcity, exacerbated by the lack of an optimized culture medium for CTC-derived organoids (CTCDOs). In this review, we summarize the origin, isolation, enrichment, culture, validation, and clinical application of CTCs and CTCDOs.
{"title":"The culture and application of circulating tumor cell-derived organoids.","authors":"Can Pan, Xueping Wang, Chuan Yang, Kai Fu, Fang Wang, Liwu Fu","doi":"10.1016/j.tcb.2024.10.004","DOIUrl":"https://doi.org/10.1016/j.tcb.2024.10.004","url":null,"abstract":"<p><p>Circulating tumor cells (CTCs), which have the heterogeneity and histological properties of the primary tumor and metastases, are shed from the primary tumor and/or metastatic lesions into the vasculature and initiate metastases at remote sites. In the clinic, CTCs are used extensively in liquid biopsies for early screening, diagnosis, treatment, and prognosis. Current research focuses on using CTC-derived models to study tumor heterogeneity and metastasis, with 3D organoids emerging as a promising tool in cancer research and precision oncology. However, isolating and enriching CTCs from blood remains challenging due to their scarcity, exacerbated by the lack of an optimized culture medium for CTC-derived organoids (CTCDOs). In this review, we summarize the origin, isolation, enrichment, culture, validation, and clinical application of CTCs and CTCDOs.</p>","PeriodicalId":56085,"journal":{"name":"Trends in Cell Biology","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142633160","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 : 2024-11-08DOI: 10.1016/j.tcb.2024.10.005
Na Zhang, Yuanxin Yang, Daichao Xu
Pyroptosis is a lytic, proinflammatory type of programmed cell death crucial for the immune response to pathogen infections and internal danger signals. Gasdermin D (GSDMD) acts as the pore-forming protein in pyroptosis following inflammasome activation. While recent research has improved our understanding of pyroptosis activation and execution, many aspects regarding the molecular mechanisms controlling inflammasome and GSDMD activation remain to be elucidated. A growing body of literature has shown that S-palmitoylation, a reversible post-translational modification (PTM) that attaches palmitate to cysteine residues, contributes to multi-layered regulation of pyroptosis. This review summarizes the emerging roles of S-palmitoylation in pyroptosis research with a focus on mechanisms that regulate NLRP3 inflammasome and GSDMD activation.
{"title":"Emerging roles of palmitoylation in pyroptosis.","authors":"Na Zhang, Yuanxin Yang, Daichao Xu","doi":"10.1016/j.tcb.2024.10.005","DOIUrl":"https://doi.org/10.1016/j.tcb.2024.10.005","url":null,"abstract":"<p><p>Pyroptosis is a lytic, proinflammatory type of programmed cell death crucial for the immune response to pathogen infections and internal danger signals. Gasdermin D (GSDMD) acts as the pore-forming protein in pyroptosis following inflammasome activation. While recent research has improved our understanding of pyroptosis activation and execution, many aspects regarding the molecular mechanisms controlling inflammasome and GSDMD activation remain to be elucidated. A growing body of literature has shown that S-palmitoylation, a reversible post-translational modification (PTM) that attaches palmitate to cysteine residues, contributes to multi-layered regulation of pyroptosis. This review summarizes the emerging roles of S-palmitoylation in pyroptosis research with a focus on mechanisms that regulate NLRP3 inflammasome and GSDMD activation.</p>","PeriodicalId":56085,"journal":{"name":"Trends in Cell Biology","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142633146","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 : 2024-11-07DOI: 10.1016/j.tcb.2024.10.006
Jennifer Jansen, Matthias Dobbelstein
Recent studies revealed how nucleolar stress enhances MDM4 exon skipping and activates p53 via the ribosomal protein L22 (RPL22; eL22). Tumor-associated L22 mutations lead to full-length MDM4 synthesis, overcoming tumor suppression by p53. This forum article explores how MDM4 splicing patterns integrate stress signaling to take p53-dependent cell fate decisions.
{"title":"MDM4 exon skipping upon dysfunctional ribosome assembly.","authors":"Jennifer Jansen, Matthias Dobbelstein","doi":"10.1016/j.tcb.2024.10.006","DOIUrl":"https://doi.org/10.1016/j.tcb.2024.10.006","url":null,"abstract":"<p><p>Recent studies revealed how nucleolar stress enhances MDM4 exon skipping and activates p53 via the ribosomal protein L22 (RPL22; eL22). Tumor-associated L22 mutations lead to full-length MDM4 synthesis, overcoming tumor suppression by p53. This forum article explores how MDM4 splicing patterns integrate stress signaling to take p53-dependent cell fate decisions.</p>","PeriodicalId":56085,"journal":{"name":"Trends in Cell Biology","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142633158","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 : 2024-11-07DOI: 10.1016/j.tcb.2024.10.007
Ninon Very, Bart Staels, Jérôme Eeckhoute
Increased protein O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) has emerged as a hallmark of mammalian cell activation, contributing to Warburg-like metabolic rewiring allowing the acquisition of new functionalities. Recent advances indicate that O-GlcNAcylation promotes the activity of transcriptional regulators driving gene expression reprogramming. This may offer new therapeutic opportunities in a broad spectrum of pathological conditions.
{"title":"Increased O-GlcNAcylation connects metabolic to transcriptional reprogramming during pathophysiological cell activation.","authors":"Ninon Very, Bart Staels, Jérôme Eeckhoute","doi":"10.1016/j.tcb.2024.10.007","DOIUrl":"https://doi.org/10.1016/j.tcb.2024.10.007","url":null,"abstract":"<p><p>Increased protein O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) has emerged as a hallmark of mammalian cell activation, contributing to Warburg-like metabolic rewiring allowing the acquisition of new functionalities. Recent advances indicate that O-GlcNAcylation promotes the activity of transcriptional regulators driving gene expression reprogramming. This may offer new therapeutic opportunities in a broad spectrum of pathological conditions.</p>","PeriodicalId":56085,"journal":{"name":"Trends in Cell Biology","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142633154","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 : 2024-11-04DOI: 10.1016/j.tcb.2024.10.001
Ivan Milenkovic, Eva Maria Novoa
Ribosomal RNAs (rRNA) are the most abundant RNA molecules in almost all cell types. The general consensus in the field is that rRNA modifications are largely species-specific, with most previous works and databases solely stratifying modifications by the species of origin, without taking other levels of complexity into account. However, new evidence has emerged suggesting dynamic rRNA modifications may have additional layers of complexity and might play an important role in development and disease. In this review article, we summarize recent evidence supporting heterogeneity and dynamics in rRNA modifications in diverse biological contexts, challenging the simplistic view of 'one-species-one-rRNA-modification-pattern'. Moreover, we highlight how rRNA modification dynamics have been studied to date and how long-read sequencing methods can significantly improve our understanding of this largely unexplored yet highly abundant RNA family, across tissues, developmental stages, and diseases.
{"title":"Dynamic rRNA modifications as a source of ribosome heterogeneity.","authors":"Ivan Milenkovic, Eva Maria Novoa","doi":"10.1016/j.tcb.2024.10.001","DOIUrl":"https://doi.org/10.1016/j.tcb.2024.10.001","url":null,"abstract":"<p><p>Ribosomal RNAs (rRNA) are the most abundant RNA molecules in almost all cell types. The general consensus in the field is that rRNA modifications are largely species-specific, with most previous works and databases solely stratifying modifications by the species of origin, without taking other levels of complexity into account. However, new evidence has emerged suggesting dynamic rRNA modifications may have additional layers of complexity and might play an important role in development and disease. In this review article, we summarize recent evidence supporting heterogeneity and dynamics in rRNA modifications in diverse biological contexts, challenging the simplistic view of 'one-species-one-rRNA-modification-pattern'. Moreover, we highlight how rRNA modification dynamics have been studied to date and how long-read sequencing methods can significantly improve our understanding of this largely unexplored yet highly abundant RNA family, across tissues, developmental stages, and diseases.</p>","PeriodicalId":56085,"journal":{"name":"Trends in Cell Biology","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142585245","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 : 2024-11-01Epub Date: 2024-05-21DOI: 10.1016/j.tcb.2024.03.007
Hope E Merens, Karine Choquet, Autum R Baxter-Koenigs, L Stirling Churchman
Splicing is a highly regulated process critical for proper pre-mRNA maturation and the maintenance of a healthy cellular environment. Splicing events are impacted by ongoing transcription, neighboring splicing events, and cis and trans regulatory factors on the respective pre-mRNA transcript. Within this complex regulatory environment, splicing kinetics have the potential to influence splicing outcomes but have historically been challenging to study in vivo. In this review, we highlight recent technological advancements that have enabled measurements of global splicing kinetics and of the variability of splicing kinetics at single introns. We demonstrate how identifying features that are correlated with splicing kinetics has increased our ability to form potential models for how splicing kinetics may be regulated in vivo.
{"title":"Timing is everything: advances in quantifying splicing kinetics.","authors":"Hope E Merens, Karine Choquet, Autum R Baxter-Koenigs, L Stirling Churchman","doi":"10.1016/j.tcb.2024.03.007","DOIUrl":"10.1016/j.tcb.2024.03.007","url":null,"abstract":"<p><p>Splicing is a highly regulated process critical for proper pre-mRNA maturation and the maintenance of a healthy cellular environment. Splicing events are impacted by ongoing transcription, neighboring splicing events, and cis and trans regulatory factors on the respective pre-mRNA transcript. Within this complex regulatory environment, splicing kinetics have the potential to influence splicing outcomes but have historically been challenging to study in vivo. In this review, we highlight recent technological advancements that have enabled measurements of global splicing kinetics and of the variability of splicing kinetics at single introns. We demonstrate how identifying features that are correlated with splicing kinetics has increased our ability to form potential models for how splicing kinetics may be regulated in vivo.</p>","PeriodicalId":56085,"journal":{"name":"Trends in Cell Biology","volume":" ","pages":"968-981"},"PeriodicalIF":13.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141081871","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 : 2024-11-01Epub Date: 2024-10-07DOI: 10.1016/j.tcb.2024.09.002
Chenghao Yan, Xu Liu, Haodong Xu, Liming Wang
Upon various stresses, mtDNA leaks from mitochondria into the cytoplasm, leading to cellular dysfunction and inflammation, thereby exacerbating disease progression. The autophagy-lysosome pathway has emerged as a pivotal quality control mechanism for eliminating abnormal cytoplasmic mtDNA. This article summarizes the mechanisms underlying mtDNA-triggered inflammation and how cytoplasmic mtDNA is eliminated.
{"title":"Cytoplasmic mtDNA clearance suppresses inflammatory immune responses.","authors":"Chenghao Yan, Xu Liu, Haodong Xu, Liming Wang","doi":"10.1016/j.tcb.2024.09.002","DOIUrl":"10.1016/j.tcb.2024.09.002","url":null,"abstract":"<p><p>Upon various stresses, mtDNA leaks from mitochondria into the cytoplasm, leading to cellular dysfunction and inflammation, thereby exacerbating disease progression. The autophagy-lysosome pathway has emerged as a pivotal quality control mechanism for eliminating abnormal cytoplasmic mtDNA. This article summarizes the mechanisms underlying mtDNA-triggered inflammation and how cytoplasmic mtDNA is eliminated.</p>","PeriodicalId":56085,"journal":{"name":"Trends in Cell Biology","volume":" ","pages":"897-900"},"PeriodicalIF":13.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142395611","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}