Pub Date : 2026-02-18DOI: 10.1038/s41580-026-00947-3
Alina Sigaeva, Charlotte Hutchings, Anthony Cesnik, Kathryn S Lilley, Emma Lundberg
Biological functions depend on the spatiotemporal distribution of proteins within cells. Key cellular activities such as signal transduction, metabolism, cell cycle and cell death are driven by the interactions of proteins that are localized in multiple cellular compartments. Such multilocalization can even allow protein with identical sequences to display multifunctionality, a phenomenon known as moonlighting. Despite its biological importance, the relationship between protein localization and function remains underexplored. In this Review, we discuss the known mechanisms of protein localization (including RNA transport, role of proteoforms and molecular interactions) and how subcellular localization controls protein function. Proper regulation of protein localization is crucial for specialized cell and tissue functions, including cell differentiation, polarization and the epithelial-mesenchymal transition. Protein mislocalization can also have important roles in pathological processes, such as in cancer, neurodegeneration and autoimmunity. We end with a discussion of current technological and conceptual challenges in the field of subcellular proteomics and spatial biology. Addressing these challenges will allow us to link the dynamic nature of protein localization and function across biological scales and contexts, with great impact on fundamental cell biology and clinical applications.
{"title":"Subcellular localization as a driver of protein function.","authors":"Alina Sigaeva, Charlotte Hutchings, Anthony Cesnik, Kathryn S Lilley, Emma Lundberg","doi":"10.1038/s41580-026-00947-3","DOIUrl":"https://doi.org/10.1038/s41580-026-00947-3","url":null,"abstract":"<p><p>Biological functions depend on the spatiotemporal distribution of proteins within cells. Key cellular activities such as signal transduction, metabolism, cell cycle and cell death are driven by the interactions of proteins that are localized in multiple cellular compartments. Such multilocalization can even allow protein with identical sequences to display multifunctionality, a phenomenon known as moonlighting. Despite its biological importance, the relationship between protein localization and function remains underexplored. In this Review, we discuss the known mechanisms of protein localization (including RNA transport, role of proteoforms and molecular interactions) and how subcellular localization controls protein function. Proper regulation of protein localization is crucial for specialized cell and tissue functions, including cell differentiation, polarization and the epithelial-mesenchymal transition. Protein mislocalization can also have important roles in pathological processes, such as in cancer, neurodegeneration and autoimmunity. We end with a discussion of current technological and conceptual challenges in the field of subcellular proteomics and spatial biology. Addressing these challenges will allow us to link the dynamic nature of protein localization and function across biological scales and contexts, with great impact on fundamental cell biology and clinical applications.</p>","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":90.2,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146220354","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 : 2026-02-17DOI: 10.1038/s41580-026-00953-5
Constantin R. Krüger
In this Tools of the Trade article, Krueger (Lorenz lab) discusses laser flash melting of cryo-electron microscopy (cryo-EM) samples for the detection of short-lived protein configurations, enabling microsecond time-resolved cryo-EM and opening new possibilities for capturing rapid structural transitions.
{"title":"Extending microsecond time-resolved cryo-electron microscopy with laser flash melting","authors":"Constantin R. Krüger","doi":"10.1038/s41580-026-00953-5","DOIUrl":"10.1038/s41580-026-00953-5","url":null,"abstract":"In this Tools of the Trade article, Krueger (Lorenz lab) discusses laser flash melting of cryo-electron microscopy (cryo-EM) samples for the detection of short-lived protein configurations, enabling microsecond time-resolved cryo-EM and opening new possibilities for capturing rapid structural transitions.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"27 5","pages":"340-340"},"PeriodicalIF":90.2,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146204957","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}
Human mitochondrial ribosomes (mitoribosomes) synthesize the 13 mitochondrial-encoded proteins of the oxidative phosphorylation machinery in a coordinated manner, ensuring proper folding of nascent peptides into the inner mitochondrial membrane and their dynamic assembly with nuclear-encoded oxidative phosphorylation components. Our understanding of mitochondrial translation is rapidly advancing, and in this Review, we discuss recent studies that reveal the intricate regulation of mitochondrial translation initiation, elongation and termination, ribosome biogenesis, redox sensing, mitochondrial mRNA maturation, and quality control mechanisms such as mitoribosome rescue. High-resolution structural studies, mitoribosome profiling and other innovative methodologies provide comprehensive insights into these regulatory networks. We also discuss pathological consequences of mitochondrial translation dysfunction, particularly antibiotic-induced ribosome stalling, which can have severe side effects in some individuals and therapeutic benefits in others. Relatedly, we discuss the emerging roles and clinical relevance of mitochondrial protein synthesis in cancer and immunity. Finally, we outline future directions in the field, including in vitro reconstitution of mitochondrial translation, gene editing in mitochondrial DNA and therapeutic applications.
{"title":"Mechanisms and disease relevance of mitochondrial translation in humans.","authors":"Ricarda Richter-Dennerlein, Xaquin Castro Dopico, Joanna Rorbach","doi":"10.1038/s41580-026-00948-2","DOIUrl":"https://doi.org/10.1038/s41580-026-00948-2","url":null,"abstract":"<p><p>Human mitochondrial ribosomes (mitoribosomes) synthesize the 13 mitochondrial-encoded proteins of the oxidative phosphorylation machinery in a coordinated manner, ensuring proper folding of nascent peptides into the inner mitochondrial membrane and their dynamic assembly with nuclear-encoded oxidative phosphorylation components. Our understanding of mitochondrial translation is rapidly advancing, and in this Review, we discuss recent studies that reveal the intricate regulation of mitochondrial translation initiation, elongation and termination, ribosome biogenesis, redox sensing, mitochondrial mRNA maturation, and quality control mechanisms such as mitoribosome rescue. High-resolution structural studies, mitoribosome profiling and other innovative methodologies provide comprehensive insights into these regulatory networks. We also discuss pathological consequences of mitochondrial translation dysfunction, particularly antibiotic-induced ribosome stalling, which can have severe side effects in some individuals and therapeutic benefits in others. Relatedly, we discuss the emerging roles and clinical relevance of mitochondrial protein synthesis in cancer and immunity. Finally, we outline future directions in the field, including in vitro reconstitution of mitochondrial translation, gene editing in mitochondrial DNA and therapeutic applications.</p>","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":90.2,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146195112","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 : 2026-01-29DOI: 10.1038/s41580-026-00950-8
Lisa Heinke
Liquid–liquid phase separation of the endoplasmic reticulum (ER)-resident protein PDZD8 leads to the formation of biomolecular condensates that stabilize ER–mitochondria contact sites.
{"title":"Organelles stick together through PDZD8-mediated condensate formation","authors":"Lisa Heinke","doi":"10.1038/s41580-026-00950-8","DOIUrl":"10.1038/s41580-026-00950-8","url":null,"abstract":"Liquid–liquid phase separation of the endoplasmic reticulum (ER)-resident protein PDZD8 leads to the formation of biomolecular condensates that stabilize ER–mitochondria contact sites.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"27 3","pages":"175-175"},"PeriodicalIF":90.2,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073091","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 : 2026-01-16DOI: 10.1038/s41580-026-00946-4
Luca Mariani
In this Tools of the Trade article, Mariani (Bulyk Lab) describes the development of PIONEAR-Seq, a method designed to explore how genome composition influences transcription factor binding, particularly in the context of nucleosomes and other genomic elements.
{"title":"PIONEARing how DNA sequence composition tunes TF–nucleosome interactions","authors":"Luca Mariani","doi":"10.1038/s41580-026-00946-4","DOIUrl":"10.1038/s41580-026-00946-4","url":null,"abstract":"In this Tools of the Trade article, Mariani (Bulyk Lab) describes the development of PIONEAR-Seq, a method designed to explore how genome composition influences transcription factor binding, particularly in the context of nucleosomes and other genomic elements.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"27 4","pages":"255-255"},"PeriodicalIF":90.2,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986518","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 : 2026-01-15DOI: 10.1038/s41580-025-00945-x
W Mike Henne,Sarah Cohen
Lipid droplets (LDs) are emerging as key factors in cellular physiology, with roles beyond energy storage, including metabolic homeostasis, signalling and development. Together with a growing list of functions, diverse LD populations are being identified in different tissue types as well as within the context of single cells. Here we summarize recent work highlighting LD diversity from three perspectives: their lipid and protein compositional heterogeneity; differences in abundance, size and spatial organization within cells; and the diverse contacts they form with other organelles, all of which contribute to LD function. We also discuss tools and approaches used to visualize LD heterogeneity, the role of LDs in pathophysiology and disease, and open questions in the field.
{"title":"Heterogeneity, dynamics and organelle interactions of lipid droplets.","authors":"W Mike Henne,Sarah Cohen","doi":"10.1038/s41580-025-00945-x","DOIUrl":"https://doi.org/10.1038/s41580-025-00945-x","url":null,"abstract":"Lipid droplets (LDs) are emerging as key factors in cellular physiology, with roles beyond energy storage, including metabolic homeostasis, signalling and development. Together with a growing list of functions, diverse LD populations are being identified in different tissue types as well as within the context of single cells. Here we summarize recent work highlighting LD diversity from three perspectives: their lipid and protein compositional heterogeneity; differences in abundance, size and spatial organization within cells; and the diverse contacts they form with other organelles, all of which contribute to LD function. We also discuss tools and approaches used to visualize LD heterogeneity, the role of LDs in pathophysiology and disease, and open questions in the field.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"15 4 1","pages":""},"PeriodicalIF":112.7,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986519","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 : 2026-01-09DOI: 10.1038/s41580-025-00944-y
Masaaki Komatsu,Nobuo N Noda,Toshifumi Inada
UFMylation is a ubiquitin-like post-translational modification that has a central role in ribosome-associated quality control at the endoplasmic reticulum (ER-RQC). Through a dedicated enzymatic cascade, UFM1 is conjugated to select substrates, notably the 60S ribosomal subunit protein RPL26, to maintain endoplasmic reticulum and ribosomal integrity under cellular stress. This Review focuses on the structural and mechanistic basis of UFMylation in ER-RQC and its contribution to proteostasis. Although recent studies have identified a growing number of putative UFM1-modified proteins across diverse cellular pathways, the physiological importance of many of these substrates remains unclear. We highlight both the emerging functional breadth of UFMylation and the need for caution in interpreting substrate relevance. UFMylation is increasingly linked to disease, including neurodevelopmental disorders and cancer, underscoring its biological importance. Together, these findings position UFMylation as a key regulatory system connecting endoplasmic reticulum function to broader stress responses.
{"title":"The mechanistic basis and cellular functions of UFMylation.","authors":"Masaaki Komatsu,Nobuo N Noda,Toshifumi Inada","doi":"10.1038/s41580-025-00944-y","DOIUrl":"https://doi.org/10.1038/s41580-025-00944-y","url":null,"abstract":"UFMylation is a ubiquitin-like post-translational modification that has a central role in ribosome-associated quality control at the endoplasmic reticulum (ER-RQC). Through a dedicated enzymatic cascade, UFM1 is conjugated to select substrates, notably the 60S ribosomal subunit protein RPL26, to maintain endoplasmic reticulum and ribosomal integrity under cellular stress. This Review focuses on the structural and mechanistic basis of UFMylation in ER-RQC and its contribution to proteostasis. Although recent studies have identified a growing number of putative UFM1-modified proteins across diverse cellular pathways, the physiological importance of many of these substrates remains unclear. We highlight both the emerging functional breadth of UFMylation and the need for caution in interpreting substrate relevance. UFMylation is increasingly linked to disease, including neurodevelopmental disorders and cancer, underscoring its biological importance. Together, these findings position UFMylation as a key regulatory system connecting endoplasmic reticulum function to broader stress responses.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"21 1","pages":""},"PeriodicalIF":112.7,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937745","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 : 2026-01-07DOI: 10.1038/s41580-025-00940-2
Gangshun Yi, Dimitrios Mamalis
In this Tools of the Trade article, Yi and Mamalis (Gilbert and Davis labs) discuss the development of Di-Gembodies, innovative constructs designed to overcome key challenges in applying cryo-electron microscopy to small proteins that are otherwise difficult to resolve.
{"title":"Engineered nanobodies facilitate cryo-EM studies of small proteins","authors":"Gangshun Yi, Dimitrios Mamalis","doi":"10.1038/s41580-025-00940-2","DOIUrl":"10.1038/s41580-025-00940-2","url":null,"abstract":"In this Tools of the Trade article, Yi and Mamalis (Gilbert and Davis labs) discuss the development of Di-Gembodies, innovative constructs designed to overcome key challenges in applying cryo-electron microscopy to small proteins that are otherwise difficult to resolve.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"27 3","pages":"174-174"},"PeriodicalIF":90.2,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907942","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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