Pub Date : 2024-08-01Epub Date: 2024-02-28DOI: 10.1016/j.tcb.2024.02.001
Jack Llewellyn, Simon J Hubbard, Joe Swift
Proteins are molecular machines that provide structure and perform vital transport, signalling and enzymatic roles. Proteins expressed by cells require tight regulation of their concentration, folding, localisation, and modifications; however, this state of protein homeostasis is continuously perturbed by tissue-level stresses. While cells in healthy tissues are able to buffer against these perturbations, for example, by expression of chaperone proteins, protein homeostasis is lost in ageing, and can lead to protein aggregation characteristic of protein folding diseases. Here, we review reports of a progressive disconnect between transcriptomic and proteomic regulation during cellular ageing. We discuss how age-associated changes to cellular responses to specific stressors in the tissue microenvironment are exacerbated by loss of ribosomal proteins, ribosomal pausing, and mistranslation.
{"title":"Translation is an emerging constraint on protein homeostasis in ageing.","authors":"Jack Llewellyn, Simon J Hubbard, Joe Swift","doi":"10.1016/j.tcb.2024.02.001","DOIUrl":"10.1016/j.tcb.2024.02.001","url":null,"abstract":"<p><p>Proteins are molecular machines that provide structure and perform vital transport, signalling and enzymatic roles. Proteins expressed by cells require tight regulation of their concentration, folding, localisation, and modifications; however, this state of protein homeostasis is continuously perturbed by tissue-level stresses. While cells in healthy tissues are able to buffer against these perturbations, for example, by expression of chaperone proteins, protein homeostasis is lost in ageing, and can lead to protein aggregation characteristic of protein folding diseases. Here, we review reports of a progressive disconnect between transcriptomic and proteomic regulation during cellular ageing. We discuss how age-associated changes to cellular responses to specific stressors in the tissue microenvironment are exacerbated by loss of ribosomal proteins, ribosomal pausing, and mistranslation.</p>","PeriodicalId":56085,"journal":{"name":"Trends in Cell Biology","volume":null,"pages":null},"PeriodicalIF":13.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139998342","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 : 2024-08-01DOI: 10.1016/j.tcb.2024.07.007
The accumulation of translocation intermediates in the mitochondrial import machinery threatens cellular fitness and is associated with cancer and neurodegeneration. A recent study by Weidberg and colleagues identifies ATAD1 as an ATP-driven extraction machine on the mitochondrial surface that pulls precursors into the cytosol to prevent clogging of mitochondrial import pores.
线粒体导入机制中转运中间体的积累会威胁细胞的健康,并与癌症和神经变性有关。Weidberg 及其同事最近的一项研究发现,ATAD1 是线粒体表面由 ATP 驱动的提取机器,它能将前体拉入细胞质,防止线粒体导入孔堵塞。
{"title":"The ATP-driven extractor ATAD1/Msp1 proof-reads protein translocation into mitochondria","authors":"","doi":"10.1016/j.tcb.2024.07.007","DOIUrl":"https://doi.org/10.1016/j.tcb.2024.07.007","url":null,"abstract":"<p>The accumulation of translocation intermediates in the mitochondrial import machinery threatens cellular fitness and is associated with cancer and neurodegeneration. A recent study by <span><span>Weidberg and colleagues</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg></span> identifies ATAD1 as an ATP-driven extraction machine on the mitochondrial surface that pulls precursors into the cytosol to prevent clogging of mitochondrial import pores.</p>","PeriodicalId":56085,"journal":{"name":"Trends in Cell Biology","volume":null,"pages":null},"PeriodicalIF":19.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141867495","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 : 2024-08-01Epub Date: 2024-06-06DOI: 10.1016/j.tcb.2024.05.004
Yinfeng Xu, Wei Wan
The cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway has a crucial role in combating pathogen infection. However, its aberrant activation is involved in several human disorders. Lysosomes are emerging as key negative regulators of cGAS-STING signaling. Here, we discuss the lysosomal control of cGAS-STING signaling and its implication in human disorders.
{"title":"Lysosomal control of the cGAS-STING signaling.","authors":"Yinfeng Xu, Wei Wan","doi":"10.1016/j.tcb.2024.05.004","DOIUrl":"10.1016/j.tcb.2024.05.004","url":null,"abstract":"<p><p>The cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway has a crucial role in combating pathogen infection. However, its aberrant activation is involved in several human disorders. Lysosomes are emerging as key negative regulators of cGAS-STING signaling. Here, we discuss the lysosomal control of cGAS-STING signaling and its implication in human disorders.</p>","PeriodicalId":56085,"journal":{"name":"Trends in Cell Biology","volume":null,"pages":null},"PeriodicalIF":13.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141288932","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 : 2024-08-01Epub Date: 2024-07-20DOI: 10.1016/j.tcb.2024.07.004
Liankui Zhou, Ying Liu
Mitochondria are pivotal organelles for cellular energy production and the regulation of stress responses. Recent research has elucidated complex mechanisms through which mitochondrial stress in one tissue can impact distant tissues, thereby promoting overall organismal health. Two recent studies by Shen et al. and Charmpilas et al. have demonstrated that an intact germline serves as a crucial signaling hub for the activation of the somatic mitochondrial unfolded protein response (UPRmt) in Caenorhabditis elegans.
{"title":"Germline regulation of the somatic mitochondrial stress response.","authors":"Liankui Zhou, Ying Liu","doi":"10.1016/j.tcb.2024.07.004","DOIUrl":"10.1016/j.tcb.2024.07.004","url":null,"abstract":"<p><p>Mitochondria are pivotal organelles for cellular energy production and the regulation of stress responses. Recent research has elucidated complex mechanisms through which mitochondrial stress in one tissue can impact distant tissues, thereby promoting overall organismal health. Two recent studies by Shen et al. and Charmpilas et al. have demonstrated that an intact germline serves as a crucial signaling hub for the activation of the somatic mitochondrial unfolded protein response (UPR<sup>mt</sup>) in Caenorhabditis elegans.</p>","PeriodicalId":56085,"journal":{"name":"Trends in Cell Biology","volume":null,"pages":null},"PeriodicalIF":13.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141735821","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 : 2024-08-01Epub Date: 2024-05-23DOI: 10.1016/j.tcb.2024.04.007
Terra M Kuhn, Malte Paulsen, Sara Cuylen-Haering
Over the past six decades, fluorescence-activated cell sorting (FACS) has become an essential technology for basic and clinical research by enabling the isolation of cells of interest in high throughput. Recent technological advancements have started a new era of flow cytometry. By combining the spatial resolution of microscopy with high-speed cell sorting, new instruments allow cell sorting based on simple image-derived parameters or sophisticated image analysis algorithms, thereby greatly expanding the scope of applications. In this review, we discuss the systems that are commercially available or have been described in enough methodological and engineering detail to allow their replication. We summarize their strengths and limitations and highlight applications that have the potential to transform various fields in basic life science research and clinical settings.
{"title":"Accessible high-speed image-activated cell sorting.","authors":"Terra M Kuhn, Malte Paulsen, Sara Cuylen-Haering","doi":"10.1016/j.tcb.2024.04.007","DOIUrl":"10.1016/j.tcb.2024.04.007","url":null,"abstract":"<p><p>Over the past six decades, fluorescence-activated cell sorting (FACS) has become an essential technology for basic and clinical research by enabling the isolation of cells of interest in high throughput. Recent technological advancements have started a new era of flow cytometry. By combining the spatial resolution of microscopy with high-speed cell sorting, new instruments allow cell sorting based on simple image-derived parameters or sophisticated image analysis algorithms, thereby greatly expanding the scope of applications. In this review, we discuss the systems that are commercially available or have been described in enough methodological and engineering detail to allow their replication. We summarize their strengths and limitations and highlight applications that have the potential to transform various fields in basic life science research and clinical settings.</p>","PeriodicalId":56085,"journal":{"name":"Trends in Cell Biology","volume":null,"pages":null},"PeriodicalIF":13.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141094755","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 : 2024-08-01Epub Date: 2023-11-10DOI: 10.1016/j.tcb.2023.10.007
Erik S Knudsen, Agnieszka K Witkiewicz, Seth M Rubin
In the commonly accepted paradigm for control of the mammalian cell cycle, sequential cyclin-dependent kinase (CDK) and cyclin activities drive the orderly transition from G1 to S phase. However, recent studies using different technological approaches and examining a broad range of cancer cell types are challenging this established paradigm. An alternative model is evolving in which cell cycles utilize different drivers and take different trajectories through the G1/S transition. We are discovering that cancer cells in particular can adapt their drivers and trajectories, which has important implications for antiproliferative therapies. These studies have helped to refine an understanding of how CDK inhibition impinges on proliferation and have significance for understanding fundamental features of cell biology and cancer.
{"title":"Cancer takes many paths through G1/S.","authors":"Erik S Knudsen, Agnieszka K Witkiewicz, Seth M Rubin","doi":"10.1016/j.tcb.2023.10.007","DOIUrl":"10.1016/j.tcb.2023.10.007","url":null,"abstract":"<p><p>In the commonly accepted paradigm for control of the mammalian cell cycle, sequential cyclin-dependent kinase (CDK) and cyclin activities drive the orderly transition from G1 to S phase. However, recent studies using different technological approaches and examining a broad range of cancer cell types are challenging this established paradigm. An alternative model is evolving in which cell cycles utilize different drivers and take different trajectories through the G1/S transition. We are discovering that cancer cells in particular can adapt their drivers and trajectories, which has important implications for antiproliferative therapies. These studies have helped to refine an understanding of how CDK inhibition impinges on proliferation and have significance for understanding fundamental features of cell biology and cancer.</p>","PeriodicalId":56085,"journal":{"name":"Trends in Cell Biology","volume":null,"pages":null},"PeriodicalIF":13.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11082069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89720870","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 : 2024-07-29DOI: 10.1016/j.tcb.2024.07.005
Sebastian Müller, Tatiana Cañeque, Stéphanie Solier, Raphaël Rodriguez
Whereas genetic mutations can alter cell properties, nongenetic mechanisms can drive rapid and reversible adaptations to changes in their physical environment, a phenomenon termed 'cell-state transition'. Metals, in particular copper and iron, have been shown to be rate-limiting catalysts of cell-state transitions controlling key chemical reactions in mitochondria and the cell nucleus, which govern metabolic and epigenetic changes underlying the acquisition of distinct cell phenotypes. Acquisition of a distinct cell identity, independently of genetic alterations, is an underlying phenomenon of various biological processes, including development, inflammation, erythropoiesis, aging, and cancer. Here, mechanisms that have been uncovered related to the role of these metals in the regulation of cell plasticity are described, illustrating how copper and iron can be exploited for therapeutic intervention.
{"title":"Copper and iron orchestrate cell-state transitions in cancer and immunity.","authors":"Sebastian Müller, Tatiana Cañeque, Stéphanie Solier, Raphaël Rodriguez","doi":"10.1016/j.tcb.2024.07.005","DOIUrl":"https://doi.org/10.1016/j.tcb.2024.07.005","url":null,"abstract":"<p><p>Whereas genetic mutations can alter cell properties, nongenetic mechanisms can drive rapid and reversible adaptations to changes in their physical environment, a phenomenon termed 'cell-state transition'. Metals, in particular copper and iron, have been shown to be rate-limiting catalysts of cell-state transitions controlling key chemical reactions in mitochondria and the cell nucleus, which govern metabolic and epigenetic changes underlying the acquisition of distinct cell phenotypes. Acquisition of a distinct cell identity, independently of genetic alterations, is an underlying phenomenon of various biological processes, including development, inflammation, erythropoiesis, aging, and cancer. Here, mechanisms that have been uncovered related to the role of these metals in the regulation of cell plasticity are described, illustrating how copper and iron can be exploited for therapeutic intervention.</p>","PeriodicalId":56085,"journal":{"name":"Trends in Cell Biology","volume":null,"pages":null},"PeriodicalIF":13.0,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141857265","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 : 2024-07-25DOI: 10.1016/j.tcb.2024.06.004
Maria Laura Sosa Ponce, Jennifer A Cobb, Vanina Zaremberg
Recent studies in yeast reveal an intricate interplay between nuclear envelope (NE) architecture and lipid metabolism, and between lipid signaling and both epigenome and genome integrity. In this review, we highlight the reciprocal connection between lipids and histone modifications, which enable metabolic reprogramming in response to nutrients. The endoplasmic reticulum (ER)-NE regulates the compartmentalization and temporal availability of epigenetic metabolites and its lipid composition also impacts nuclear processes, such as transcriptional silencing and the DNA damage response (DDR). We also discuss recent work providing mechanistic insight into lipid droplet (LD) formation and sterols in the nucleus, and the collective data showing Opi1 as a central factor in both membrane sensing and transcriptional regulation of lipid-chromatin interrelated processes.
最近的酵母研究揭示了核包膜(NE)结构与脂质代谢之间以及脂质信号转导与表观基因组和基因组完整性之间错综复杂的相互作用。在这篇综述中,我们将重点介绍脂质与组蛋白修饰之间的相互联系,这种联系能使代谢重编程对营养物质做出响应。内质网(ER)-NE 调节着表观遗传代谢产物的分区和时间可用性,其脂质组成也影响着转录沉默和 DNA 损伤应答(DDR)等核过程。我们还讨论了最近的工作,这些工作提供了对细胞核中脂滴(LD)形成和固醇的机理认识,以及显示 Opi1 是膜感应和转录调控脂质-染色质相互关联过程的核心因子的集体数据。
{"title":"Lipids and chromatin: a tale of intriguing connections shaping genomic landscapes.","authors":"Maria Laura Sosa Ponce, Jennifer A Cobb, Vanina Zaremberg","doi":"10.1016/j.tcb.2024.06.004","DOIUrl":"10.1016/j.tcb.2024.06.004","url":null,"abstract":"<p><p>Recent studies in yeast reveal an intricate interplay between nuclear envelope (NE) architecture and lipid metabolism, and between lipid signaling and both epigenome and genome integrity. In this review, we highlight the reciprocal connection between lipids and histone modifications, which enable metabolic reprogramming in response to nutrients. The endoplasmic reticulum (ER)-NE regulates the compartmentalization and temporal availability of epigenetic metabolites and its lipid composition also impacts nuclear processes, such as transcriptional silencing and the DNA damage response (DDR). We also discuss recent work providing mechanistic insight into lipid droplet (LD) formation and sterols in the nucleus, and the collective data showing Opi1 as a central factor in both membrane sensing and transcriptional regulation of lipid-chromatin interrelated processes.</p>","PeriodicalId":56085,"journal":{"name":"Trends in Cell Biology","volume":null,"pages":null},"PeriodicalIF":13.0,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141768066","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 : 2024-07-24DOI: 10.1016/j.tcb.2024.07.003
Claudia Morganti, Massimo Bonora, Keisuke Ito
Mitochondrial metabolism plays a central role in the regulation of hematopoietic stem cell (HSC) biology. Mitochondrial fatty acid oxidation (FAO) is pivotal in controlling HSC self-renewal and differentiation. Herein, we discuss recent evidence suggesting that NADPH generated in the mitochondria can influence the fate of HSCs. Although NADPH has multiple functions, HSCs show high levels of NADPH that are preferentially used for cholesterol biosynthesis. Endogenous cholesterol supports the biogenesis of extracellular vesicles (EVs), which are essential for maintaining HSC properties. We also highlight the significance of EVs in hematopoiesis through autocrine signaling. Elucidating the mitochondrial NADPH-cholesterol axis as part of the metabolic requirements of healthy HSCs will facilitate the development of new therapies for hematological disorders.
{"title":"Metabolism and HSC fate: what NADPH is made for.","authors":"Claudia Morganti, Massimo Bonora, Keisuke Ito","doi":"10.1016/j.tcb.2024.07.003","DOIUrl":"10.1016/j.tcb.2024.07.003","url":null,"abstract":"<p><p>Mitochondrial metabolism plays a central role in the regulation of hematopoietic stem cell (HSC) biology. Mitochondrial fatty acid oxidation (FAO) is pivotal in controlling HSC self-renewal and differentiation. Herein, we discuss recent evidence suggesting that NADPH generated in the mitochondria can influence the fate of HSCs. Although NADPH has multiple functions, HSCs show high levels of NADPH that are preferentially used for cholesterol biosynthesis. Endogenous cholesterol supports the biogenesis of extracellular vesicles (EVs), which are essential for maintaining HSC properties. We also highlight the significance of EVs in hematopoiesis through autocrine signaling. Elucidating the mitochondrial NADPH-cholesterol axis as part of the metabolic requirements of healthy HSCs will facilitate the development of new therapies for hematological disorders.</p>","PeriodicalId":56085,"journal":{"name":"Trends in Cell Biology","volume":null,"pages":null},"PeriodicalIF":13.0,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141762960","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 : 2024-07-24DOI: 10.1016/j.tcb.2024.07.002
Clementine E Philibert, Mikel Garcia-Marcos
G-protein-coupled receptors (GPCRs) are essential mediators of neuromodulation and prominent pharmacological targets. While activation of heterotrimeric G-proteins (Gαβɣ) by GPCRs is essential in this process, much less is known about the postreceptor mechanisms that influence G-protein activity. Neurons express G-protein regulators that shape the amplitude and kinetics of GPCR-mediated synaptic responses. Although many of these operate by directly altering how G-proteins handle guanine-nucleotides enzymatically, recent discoveries have revealed alternative mechanisms by which GPCR-stimulated G-protein responses are modulated at the synapse. In this review, we cover the molecular basis for, and consequences of, the action of two G-protein regulators that do not affect the enzymatic activity of G-proteins directly: Gα inhibitory interacting protein (GINIP), which binds active Gα subunits, and potassium channel tetramerization domain-containing 12 (KCTD12), which binds active Gβγ subunits.
G 蛋白偶联受体(GPCR)是神经调节的重要介质,也是重要的药理靶标。虽然 GPCR 对异源三聚体 G 蛋白(Gαβɣ)的激活在这一过程中至关重要,但人们对影响 G 蛋白活性的受体后机制知之甚少。神经元表达的 G 蛋白调节因子可影响 GPCR 介导的突触反应的幅度和动力学。虽然其中许多调节剂是通过直接改变 G 蛋白如何酶促处理鸟嘌呤核苷酸来发挥作用的,但最近的发现揭示了 GPCR 刺激的 G 蛋白反应在突触处受到调节的其他机制。在这篇综述中,我们将介绍两种不直接影响 G 蛋白酶活性的 G 蛋白调节剂作用的分子基础和后果:Gα抑制性相互作用蛋白(GINIP)能与活性Gα亚基结合,而含钾通道四聚体化结构域的12(KCTD12)能与活性Gβγ亚基结合。
{"title":"Smooth operator(s): dialing up and down neurotransmitter responses by G-protein regulators.","authors":"Clementine E Philibert, Mikel Garcia-Marcos","doi":"10.1016/j.tcb.2024.07.002","DOIUrl":"https://doi.org/10.1016/j.tcb.2024.07.002","url":null,"abstract":"<p><p>G-protein-coupled receptors (GPCRs) are essential mediators of neuromodulation and prominent pharmacological targets. While activation of heterotrimeric G-proteins (Gαβɣ) by GPCRs is essential in this process, much less is known about the postreceptor mechanisms that influence G-protein activity. Neurons express G-protein regulators that shape the amplitude and kinetics of GPCR-mediated synaptic responses. Although many of these operate by directly altering how G-proteins handle guanine-nucleotides enzymatically, recent discoveries have revealed alternative mechanisms by which GPCR-stimulated G-protein responses are modulated at the synapse. In this review, we cover the molecular basis for, and consequences of, the action of two G-protein regulators that do not affect the enzymatic activity of G-proteins directly: Gα inhibitory interacting protein (GINIP), which binds active Gα subunits, and potassium channel tetramerization domain-containing 12 (KCTD12), which binds active Gβγ subunits.</p>","PeriodicalId":56085,"journal":{"name":"Trends in Cell Biology","volume":null,"pages":null},"PeriodicalIF":13.0,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141762961","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}