Pub Date : 2024-07-02DOI: 10.1038/s41556-024-01444-5
Marina Chekulaeva
The importance of subcellular mRNA localization is well established, but the underlying mechanisms mostly remain an enigma. Early studies suggested that specific mRNA sequences recruit RNA-binding proteins (RBPs) to regulate mRNA localization. However, despite the observation of thousands of localized mRNAs, only a handful of these sequences and RBPs have been identified. This suggests the existence of alternative, and possibly predominant, mechanisms for mRNA localization. Here I re-examine currently described mRNA localization mechanisms and explore alternative models that could account for its widespread occurrence. The subcellular localization of numerous mRNAs has been demonstrated. This Review presents the different means of mRNA localization described and discusses how they can account for the widespread occurrence of this phenomenon.
{"title":"Mechanistic insights into the basis of widespread RNA localization","authors":"Marina Chekulaeva","doi":"10.1038/s41556-024-01444-5","DOIUrl":"10.1038/s41556-024-01444-5","url":null,"abstract":"The importance of subcellular mRNA localization is well established, but the underlying mechanisms mostly remain an enigma. Early studies suggested that specific mRNA sequences recruit RNA-binding proteins (RBPs) to regulate mRNA localization. However, despite the observation of thousands of localized mRNAs, only a handful of these sequences and RBPs have been identified. This suggests the existence of alternative, and possibly predominant, mechanisms for mRNA localization. Here I re-examine currently described mRNA localization mechanisms and explore alternative models that could account for its widespread occurrence. The subcellular localization of numerous mRNAs has been demonstrated. This Review presents the different means of mRNA localization described and discusses how they can account for the widespread occurrence of this phenomenon.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141489156","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 : 2024-07-01DOI: 10.1038/s41556-024-01456-1
Chuchu Wang, Kai Zhang, Bin Cai, Jillian E. Haller, Kathryn E. Carnazza, Jiaojiao Hu, Chunyu Zhao, Zhiqi Tian, Xiao Hu, Daniel Hall, Jiali Qiang, Shouqiao Hou, Zhenying Liu, Jinge Gu, Yaoyang Zhang, Kim B. Seroogy, Jacqueline Burré, Yanshan Fang, Cong Liu, Axel T. Brunger, Dan Li, Jiajie Diao
α-Synuclein (α-Syn) aggregation is closely associated with Parkinson’s disease neuropathology. Physiologically, α-Syn promotes synaptic vesicle (SV) clustering and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly. However, the underlying structural and molecular mechanisms are uncertain and it is not known whether this function affects the pathological aggregation of α-Syn. Here we show that the juxtamembrane region of vesicle-associated membrane protein 2 (VAMP2)—a component of the SNARE complex that resides on SVs—directly interacts with the carboxy-terminal region of α-Syn through charged residues to regulate α-Syn’s function in clustering SVs and promoting SNARE complex assembly by inducing a multi-component condensed phase of SVs, α-Syn and other components. Moreover, VAMP2 binding protects α-Syn against forming aggregation-prone oligomers and fibrils in these condensates. Our results suggest a molecular mechanism that maintains α-Syn’s function and prevents its pathological amyloid aggregation, the failure of which may lead to Parkinson’s disease. Agarwal et al. and Wang et al. show that vesicle-associated membrane protein 2 (VAMP2) interacts with and regulates alpha-synuclein biomolecular condensation, affecting α-synuclein function, which may prevent pathological amyloid aggregation.
{"title":"VAMP2 chaperones α-synuclein in synaptic vesicle co-condensates","authors":"Chuchu Wang, Kai Zhang, Bin Cai, Jillian E. Haller, Kathryn E. Carnazza, Jiaojiao Hu, Chunyu Zhao, Zhiqi Tian, Xiao Hu, Daniel Hall, Jiali Qiang, Shouqiao Hou, Zhenying Liu, Jinge Gu, Yaoyang Zhang, Kim B. Seroogy, Jacqueline Burré, Yanshan Fang, Cong Liu, Axel T. Brunger, Dan Li, Jiajie Diao","doi":"10.1038/s41556-024-01456-1","DOIUrl":"10.1038/s41556-024-01456-1","url":null,"abstract":"α-Synuclein (α-Syn) aggregation is closely associated with Parkinson’s disease neuropathology. Physiologically, α-Syn promotes synaptic vesicle (SV) clustering and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly. However, the underlying structural and molecular mechanisms are uncertain and it is not known whether this function affects the pathological aggregation of α-Syn. Here we show that the juxtamembrane region of vesicle-associated membrane protein 2 (VAMP2)—a component of the SNARE complex that resides on SVs—directly interacts with the carboxy-terminal region of α-Syn through charged residues to regulate α-Syn’s function in clustering SVs and promoting SNARE complex assembly by inducing a multi-component condensed phase of SVs, α-Syn and other components. Moreover, VAMP2 binding protects α-Syn against forming aggregation-prone oligomers and fibrils in these condensates. Our results suggest a molecular mechanism that maintains α-Syn’s function and prevents its pathological amyloid aggregation, the failure of which may lead to Parkinson’s disease. Agarwal et al. and Wang et al. show that vesicle-associated membrane protein 2 (VAMP2) interacts with and regulates alpha-synuclein biomolecular condensation, affecting α-synuclein function, which may prevent pathological amyloid aggregation.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141475333","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 : 2024-07-01DOI: 10.1038/s41556-024-01451-6
Aishwarya Agarwal, Aswathy Chandran, Farheen Raza, Irina-Maria Ungureanu, Christine Hilcenko, Katherine Stott, Nicholas A. Bright, Nobuhiro Morone, Alan J. Warren, Janin Lautenschläger
α-Synuclein (αSYN), a pivotal synaptic protein implicated in synucleinopathies such as Parkinson’s disease and Lewy body dementia, undergoes protein phase separation. We reveal that vesicle-associated membrane protein 2 (VAMP2) orchestrates αSYN phase separation both in vitro and in cells. Electrostatic interactions, specifically mediated by VAMP2 via its juxtamembrane domain and the αSYN C-terminal region, drive phase separation. Condensate formation is specific for R-SNARE VAMP2 and dependent on αSYN lipid membrane binding. Our results delineate a regulatory mechanism for αSYN phase separation in cells. Furthermore, we show that αSYN condensates sequester vesicles and attract complexin-1 and -2, thus supporting a role in synaptic physiology and pathophysiology. Agarwal et al. show that vesicle-associated membrane protein 2 interacts with and regulates α-synuclein biomolecular condensation, affecting α-synuclein function, which may prevent pathological amyloid aggregation.
{"title":"VAMP2 regulates phase separation of α-synuclein","authors":"Aishwarya Agarwal, Aswathy Chandran, Farheen Raza, Irina-Maria Ungureanu, Christine Hilcenko, Katherine Stott, Nicholas A. Bright, Nobuhiro Morone, Alan J. Warren, Janin Lautenschläger","doi":"10.1038/s41556-024-01451-6","DOIUrl":"10.1038/s41556-024-01451-6","url":null,"abstract":"α-Synuclein (αSYN), a pivotal synaptic protein implicated in synucleinopathies such as Parkinson’s disease and Lewy body dementia, undergoes protein phase separation. We reveal that vesicle-associated membrane protein 2 (VAMP2) orchestrates αSYN phase separation both in vitro and in cells. Electrostatic interactions, specifically mediated by VAMP2 via its juxtamembrane domain and the αSYN C-terminal region, drive phase separation. Condensate formation is specific for R-SNARE VAMP2 and dependent on αSYN lipid membrane binding. Our results delineate a regulatory mechanism for αSYN phase separation in cells. Furthermore, we show that αSYN condensates sequester vesicles and attract complexin-1 and -2, thus supporting a role in synaptic physiology and pathophysiology. Agarwal et al. show that vesicle-associated membrane protein 2 interacts with and regulates α-synuclein biomolecular condensation, affecting α-synuclein function, which may prevent pathological amyloid aggregation.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01451-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141475208","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 : 2024-07-01DOI: 10.1038/s41556-024-01453-4
Yiyan Lin, Dhiman Sankar Pal, Parijat Banerjee, Tatsat Banerjee, Guanghui Qin, Yu Deng, Jane Borleis, Pablo A. Iglesias, Peter N. Devreotes
Ras has been extensively studied as a promoter of cell proliferation, whereas few studies have explored its role in migration. To investigate the direct and immediate effects of Ras activity on cell motility or polarity, we focused on RasGAPs, C2GAPB in Dictyostelium amoebae and RASAL3 in HL-60 neutrophils and macrophages. In both cellular systems, optically recruiting the respective RasGAP to the cell front extinguished pre-existing protrusions and changed migration direction. However, when these respective RasGAPs were recruited uniformly to the membrane, cells polarized and moved more rapidly, whereas targeting to the back exaggerated these effects. These unexpected outcomes of attenuating Ras activity naturally had strong, context-dependent consequences for chemotaxis. The RasGAP-mediated polarization depended critically on myosin II activity and commenced with contraction at the cell rear, followed by sustained mTORC2-dependent actin polymerization at the front. These experimental results were captured by computational simulations in which Ras levels control front- and back-promoting feedback loops. The discovery that inhibiting Ras activity can produce counterintuitive effects on cell migration has important implications for future drug-design strategies targeting oncogenic Ras. Lin, Pal, et al. report a role for localized activation of Ras activity in promoting cell polarity and motility.
{"title":"Ras suppression potentiates rear actomyosin contractility-driven cell polarization and migration","authors":"Yiyan Lin, Dhiman Sankar Pal, Parijat Banerjee, Tatsat Banerjee, Guanghui Qin, Yu Deng, Jane Borleis, Pablo A. Iglesias, Peter N. Devreotes","doi":"10.1038/s41556-024-01453-4","DOIUrl":"10.1038/s41556-024-01453-4","url":null,"abstract":"Ras has been extensively studied as a promoter of cell proliferation, whereas few studies have explored its role in migration. To investigate the direct and immediate effects of Ras activity on cell motility or polarity, we focused on RasGAPs, C2GAPB in Dictyostelium amoebae and RASAL3 in HL-60 neutrophils and macrophages. In both cellular systems, optically recruiting the respective RasGAP to the cell front extinguished pre-existing protrusions and changed migration direction. However, when these respective RasGAPs were recruited uniformly to the membrane, cells polarized and moved more rapidly, whereas targeting to the back exaggerated these effects. These unexpected outcomes of attenuating Ras activity naturally had strong, context-dependent consequences for chemotaxis. The RasGAP-mediated polarization depended critically on myosin II activity and commenced with contraction at the cell rear, followed by sustained mTORC2-dependent actin polymerization at the front. These experimental results were captured by computational simulations in which Ras levels control front- and back-promoting feedback loops. The discovery that inhibiting Ras activity can produce counterintuitive effects on cell migration has important implications for future drug-design strategies targeting oncogenic Ras. Lin, Pal, et al. report a role for localized activation of Ras activity in promoting cell polarity and motility.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141475331","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 : 2024-06-26DOI: 10.1038/s41556-024-01446-3
Marco Seehawer, Zheqi Li, Jun Nishida, Pierre Foidart, Andrew H. Reiter, Ernesto Rojas-Jimenez, Marie-Anne Goyette, Pengze Yan, Shaunak Raval, Miguel Munoz Gomez, Paloma Cejas, Henry W. Long, Malvina Papanastasiou, Kornelia Polyak
KMT2C and KMT2D, encoding histone H3 lysine 4 methyltransferases, are among the most commonly mutated genes in triple-negative breast cancer (TNBC). However, how these mutations may shape epigenomic and transcriptomic landscapes to promote tumorigenesis is largely unknown. Here we describe that deletion of Kmt2c or Kmt2d in non-metastatic murine models of TNBC drives metastasis, especially to the brain. Global chromatin profiling and chromatin immunoprecipitation followed by sequencing revealed altered H3K4me1, H3K27ac and H3K27me3 chromatin marks in knockout cells and demonstrated enhanced binding of the H3K27me3 lysine demethylase KDM6A, which significantly correlated with gene expression. We identified Mmp3 as being commonly upregulated via epigenetic mechanisms in both knockout models. Consistent with these findings, samples from patients with KMT2C-mutant TNBC have higher MMP3 levels. Downregulation or pharmacological inhibition of KDM6A diminished Mmp3 upregulation induced by the loss of histone–lysine N-methyltransferase 2 (KMT2) and prevented brain metastasis similar to direct downregulation of Mmp3. Taken together, we identified the KDM6A–matrix metalloproteinase 3 axis as a key mediator of KMT2C/D loss-driven metastasis in TNBC. Seehawer et al. show that deletion of Kmt2c or Kmt2d promotes brain metastasis in mouse models of triple-negative breast cancer due to altered KDM6A activity and upregulated MMP3 expression, which may constitute a potential therapeutic target.
{"title":"Loss of Kmt2c or Kmt2d drives brain metastasis via KDM6A-dependent upregulation of MMP3","authors":"Marco Seehawer, Zheqi Li, Jun Nishida, Pierre Foidart, Andrew H. Reiter, Ernesto Rojas-Jimenez, Marie-Anne Goyette, Pengze Yan, Shaunak Raval, Miguel Munoz Gomez, Paloma Cejas, Henry W. Long, Malvina Papanastasiou, Kornelia Polyak","doi":"10.1038/s41556-024-01446-3","DOIUrl":"10.1038/s41556-024-01446-3","url":null,"abstract":"KMT2C and KMT2D, encoding histone H3 lysine 4 methyltransferases, are among the most commonly mutated genes in triple-negative breast cancer (TNBC). However, how these mutations may shape epigenomic and transcriptomic landscapes to promote tumorigenesis is largely unknown. Here we describe that deletion of Kmt2c or Kmt2d in non-metastatic murine models of TNBC drives metastasis, especially to the brain. Global chromatin profiling and chromatin immunoprecipitation followed by sequencing revealed altered H3K4me1, H3K27ac and H3K27me3 chromatin marks in knockout cells and demonstrated enhanced binding of the H3K27me3 lysine demethylase KDM6A, which significantly correlated with gene expression. We identified Mmp3 as being commonly upregulated via epigenetic mechanisms in both knockout models. Consistent with these findings, samples from patients with KMT2C-mutant TNBC have higher MMP3 levels. Downregulation or pharmacological inhibition of KDM6A diminished Mmp3 upregulation induced by the loss of histone–lysine N-methyltransferase 2 (KMT2) and prevented brain metastasis similar to direct downregulation of Mmp3. Taken together, we identified the KDM6A–matrix metalloproteinase 3 axis as a key mediator of KMT2C/D loss-driven metastasis in TNBC. Seehawer et al. show that deletion of Kmt2c or Kmt2d promotes brain metastasis in mouse models of triple-negative breast cancer due to altered KDM6A activity and upregulated MMP3 expression, which may constitute a potential therapeutic target.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01446-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141453096","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 : 2024-06-26DOI: 10.1038/s41556-024-01458-z
Arthur W. Lambert, Yun Zhang, Robert A. Weinberg
{"title":"Publisher Correction: Cell-intrinsic and microenvironmental determinants of metastatic colonization","authors":"Arthur W. Lambert, Yun Zhang, Robert A. Weinberg","doi":"10.1038/s41556-024-01458-z","DOIUrl":"10.1038/s41556-024-01458-z","url":null,"abstract":"","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01458-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141458198","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 : 2024-06-26DOI: 10.1038/s41556-024-01445-4
Yuxin Sun, Xuan Tao, Yaping Han, Xubo Lin, Rui Tian, Haodong Wang, Pei Chang, Qiming Sun, Liang Ge, Min Zhang
Cargo translocation across membranes is a crucial aspect of secretion. In conventional secretion signal peptide-equipped proteins enter the endoplasmic reticulum (ER), whereas a subset of cargo lacking signal peptides translocate into the ER–Golgi intermediate compartment (ERGIC) in a process called unconventional protein secretion (UcPS). The regulatory events at the ERGIC in UcPS are unclear. Here we reveal the involvement of ERGIC-localized small GTPases, Rab1 (Rab1A and Rab1B) and Rab2A, in regulating UcPS cargo transport via TMED10 on the ERGIC. Rab1 enhances TMED10 translocator activity, promoting cargo translocation into the ERGIC, whereas Rab2A, in collaboration with KIF5B, regulates ERGIC compartmentalization, establishing a UcPS-specific compartment. This study highlights the pivotal role of ERGIC-localized Rabs in governing cargo translocation and specifying the ERGIC’s function in UcPS. Sun, Tao, Han et al. identify the Rabs involved in unconventional protein secretion mediated by TMED10 and in ER–Golgi intermediate compartment organization.
{"title":"A dual role of ERGIC-localized Rabs in TMED10-mediated unconventional protein secretion","authors":"Yuxin Sun, Xuan Tao, Yaping Han, Xubo Lin, Rui Tian, Haodong Wang, Pei Chang, Qiming Sun, Liang Ge, Min Zhang","doi":"10.1038/s41556-024-01445-4","DOIUrl":"10.1038/s41556-024-01445-4","url":null,"abstract":"Cargo translocation across membranes is a crucial aspect of secretion. In conventional secretion signal peptide-equipped proteins enter the endoplasmic reticulum (ER), whereas a subset of cargo lacking signal peptides translocate into the ER–Golgi intermediate compartment (ERGIC) in a process called unconventional protein secretion (UcPS). The regulatory events at the ERGIC in UcPS are unclear. Here we reveal the involvement of ERGIC-localized small GTPases, Rab1 (Rab1A and Rab1B) and Rab2A, in regulating UcPS cargo transport via TMED10 on the ERGIC. Rab1 enhances TMED10 translocator activity, promoting cargo translocation into the ERGIC, whereas Rab2A, in collaboration with KIF5B, regulates ERGIC compartmentalization, establishing a UcPS-specific compartment. This study highlights the pivotal role of ERGIC-localized Rabs in governing cargo translocation and specifying the ERGIC’s function in UcPS. Sun, Tao, Han et al. identify the Rabs involved in unconventional protein secretion mediated by TMED10 and in ER–Golgi intermediate compartment organization.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141452949","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 : 2024-06-25DOI: 10.1038/s41556-024-01450-7
Andrew J. Davidson, Rosalind Heron, Jyotirekha Das, Michael Overholtzer, Will Wood
Ferroptosis is a distinct form of necrotic cell death caused by overwhelming lipid peroxidation, and emerging evidence indicates a major contribution to organ damage in multiple pathologies. However, ferroptosis has not yet been visualized in vivo due to a lack of specific probes, which has severely limited the study of how the immune system interacts with ferroptotic cells and how this process contributes to inflammation. Consequently, whether ferroptosis has a physiological role has remained a key outstanding question. Here we identify a distinct, ferroptotic-like, necrotic cell death occurring in vivo during wounding of the Drosophila embryo using live imaging. We further demonstrate that macrophages rapidly engage these necrotic cells within the embryo but struggle to engulf them, leading to prolonged, frustrated phagocytosis and frequent corpse disintegration. Conversely, suppression of the ferroptotic programme during wounding delays macrophage recruitment to the injury site, pointing to conflicting roles for ferroptosis during inflammation in vivo. Davidson et al. visualize ferroptosis-like cell death using three-colour live imaging in vivo and demonstrate its role in triggering macrophage recruitment but delaying resolution of inflammation during wounding in the Drosophila embryo.
{"title":"Ferroptosis-like cell death promotes and prolongs inflammation in Drosophila","authors":"Andrew J. Davidson, Rosalind Heron, Jyotirekha Das, Michael Overholtzer, Will Wood","doi":"10.1038/s41556-024-01450-7","DOIUrl":"10.1038/s41556-024-01450-7","url":null,"abstract":"Ferroptosis is a distinct form of necrotic cell death caused by overwhelming lipid peroxidation, and emerging evidence indicates a major contribution to organ damage in multiple pathologies. However, ferroptosis has not yet been visualized in vivo due to a lack of specific probes, which has severely limited the study of how the immune system interacts with ferroptotic cells and how this process contributes to inflammation. Consequently, whether ferroptosis has a physiological role has remained a key outstanding question. Here we identify a distinct, ferroptotic-like, necrotic cell death occurring in vivo during wounding of the Drosophila embryo using live imaging. We further demonstrate that macrophages rapidly engage these necrotic cells within the embryo but struggle to engulf them, leading to prolonged, frustrated phagocytosis and frequent corpse disintegration. Conversely, suppression of the ferroptotic programme during wounding delays macrophage recruitment to the injury site, pointing to conflicting roles for ferroptosis during inflammation in vivo. Davidson et al. visualize ferroptosis-like cell death using three-colour live imaging in vivo and demonstrate its role in triggering macrophage recruitment but delaying resolution of inflammation during wounding in the Drosophila embryo.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01450-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141448384","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 : 2024-06-24DOI: 10.1038/s41556-024-01437-4
Phillip Wulfridge, Kavitha Sarma
R-loops are three-stranded nucleic acid structures that are abundant and widespread across the genome and that have important physiological roles in many nuclear processes. Their accumulation is observed in cancers and neurodegenerative disorders. Recent studies have implicated a function for R-loops and G-quadruplex (G4) structures, which can form on the displaced single strand of R-loops, in three-dimensional genome organization in both physiological and pathological contexts. Here we discuss the interconnected functions of DNA:RNA hybrids and G4s within R-loops, their impact on DNA repair and gene regulatory networks, and their emerging roles in genome organization during development and disease. R-loops and G-quadruplexes are non-canonical nucleic acid structures with known roles in genome organization. Here, Wulfridge and Sarma highlight emerging roles in DNA repair and transcriptional and epigenetic gene regulation.
R 环是一种三链核酸结构，在整个基因组中含量丰富，分布广泛，在许多核过程中具有重要的生理作用。在癌症和神经退行性疾病中都能观察到它们的积累。最近的研究表明，在生理和病理情况下，R-环和 G-四叠体（G4）结构在基因组的三维组织中发挥着作用，G-四叠体可在 R-环的移位单链上形成。在这里，我们将讨论 DNA:RNA 杂交体和 R 环内 G4 的相互关联功能、它们对 DNA 修复和基因调控网络的影响，以及它们在发育和疾病过程中基因组组织中的新作用。
{"title":"Intertwining roles of R-loops and G-quadruplexes in DNA repair, transcription and genome organization","authors":"Phillip Wulfridge, Kavitha Sarma","doi":"10.1038/s41556-024-01437-4","DOIUrl":"10.1038/s41556-024-01437-4","url":null,"abstract":"R-loops are three-stranded nucleic acid structures that are abundant and widespread across the genome and that have important physiological roles in many nuclear processes. Their accumulation is observed in cancers and neurodegenerative disorders. Recent studies have implicated a function for R-loops and G-quadruplex (G4) structures, which can form on the displaced single strand of R-loops, in three-dimensional genome organization in both physiological and pathological contexts. Here we discuss the interconnected functions of DNA:RNA hybrids and G4s within R-loops, their impact on DNA repair and gene regulatory networks, and their emerging roles in genome organization during development and disease. R-loops and G-quadruplexes are non-canonical nucleic acid structures with known roles in genome organization. Here, Wulfridge and Sarma highlight emerging roles in DNA repair and transcriptional and epigenetic gene regulation.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141444878","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 : 2024-06-20DOI: 10.1038/s41556-024-01429-4
Hannah L. Glover, Annabell Schreiner, Grant Dewson, Stephen W. G. Tait
Mitochondria are cellular factories for energy production, calcium homeostasis and iron metabolism, but they also have an unequivocal and central role in intrinsic apoptosis through the release of cytochrome c. While the subsequent activation of proteolytic caspases ensures that cell death proceeds in the absence of collateral inflammation, other phlogistic cell death pathways have been implicated in using, or engaging, mitochondria. Here we discuss the emerging complexities of intrinsic apoptosis controlled by the BCL-2 family of proteins. We highlight the emerging theory that non-lethal mitochondrial apoptotic signalling has diverse biological roles that impact cancer, innate immunity and ageing. Finally, we delineate the role of mitochondria in other forms of cell death, such as pyroptosis, ferroptosis and necroptosis, and discuss mitochondria as central hubs for the intersection and coordination of cell death signalling pathways, underscoring their potential for therapeutic manipulation. Several processes of regulated cell death engage or use mitochondria, which are thus central hubs that not only coordinate cell death but also elicit non-lethal signalling mediated by mitochondrial outer membrane permeabilization.
线粒体是细胞能量生产、钙平衡和铁代谢的工厂，但它们也通过释放细胞色素 c 在细胞内在凋亡中发挥着明确而核心的作用。虽然随后蛋白水解 Caspases 的激活确保了细胞死亡在没有附带炎症的情况下进行，但其他噬细胞死亡途径也牵涉到线粒体的使用或参与。在此，我们将讨论由 BCL-2 家族蛋白控制的内在凋亡的复杂性。我们强调了新出现的理论，即非致命性线粒体凋亡信号具有影响癌症、先天性免疫和衰老的多种生物学作用。最后，我们描述了线粒体在其他形式的细胞死亡（如热凋亡、铁凋亡和坏死）中的作用，并讨论了线粒体作为细胞死亡信号通路交叉和协调的中心枢纽的作用，强调了对线粒体进行治疗操作的潜力。
{"title":"Mitochondria and cell death","authors":"Hannah L. Glover, Annabell Schreiner, Grant Dewson, Stephen W. G. Tait","doi":"10.1038/s41556-024-01429-4","DOIUrl":"10.1038/s41556-024-01429-4","url":null,"abstract":"Mitochondria are cellular factories for energy production, calcium homeostasis and iron metabolism, but they also have an unequivocal and central role in intrinsic apoptosis through the release of cytochrome c. While the subsequent activation of proteolytic caspases ensures that cell death proceeds in the absence of collateral inflammation, other phlogistic cell death pathways have been implicated in using, or engaging, mitochondria. Here we discuss the emerging complexities of intrinsic apoptosis controlled by the BCL-2 family of proteins. We highlight the emerging theory that non-lethal mitochondrial apoptotic signalling has diverse biological roles that impact cancer, innate immunity and ageing. Finally, we delineate the role of mitochondria in other forms of cell death, such as pyroptosis, ferroptosis and necroptosis, and discuss mitochondria as central hubs for the intersection and coordination of cell death signalling pathways, underscoring their potential for therapeutic manipulation. Several processes of regulated cell death engage or use mitochondria, which are thus central hubs that not only coordinate cell death but also elicit non-lethal signalling mediated by mitochondrial outer membrane permeabilization.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141430489","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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