Pub Date : 2024-11-01Epub Date: 2024-09-20DOI: 10.1038/s44319-024-00250-2
Rebecca A Sager, Sarah J Backe, Diana M Dunn, Jennifer A Heritz, Elham Ahanin, Natela Dushukyan, Barry Panaretou, Gennady Bratslavsky, Mark R Woodford, Dimitra Bourboulia, Mehdi Mollapour
The serine/threonine protein phosphatase 5 (PP5) regulates hormone and stress-induced signaling networks. Unlike other phosphoprotein phosphatases, PP5 contains both regulatory and catalytic domains and is further regulated through post-translational modifications (PTMs). Here we identify that SUMOylation of K430 in the catalytic domain of PP5 regulates phosphatase activity. Additionally, phosphorylation of PP5-T362 is pre-requisite for SUMOylation, suggesting the ordered addition of PTMs regulates PP5 function in cells. Using the glucocorticoid receptor, a well known substrate for PP5, we demonstrate that SUMOylation results in substrate release from PP5. We harness this information to create a non-SUMOylatable K430R mutant as a 'substrate trap' and globally identified novel PP5 substrate candidates. Lastly, we generated a consensus dephosphorylation motif using known substrates, and verified its presence in the new candidate substrates. This study unravels the impact of cross talk of SUMOylation and phosphorylation on PP5 phosphatase activity and substrate release in cells.
{"title":"SUMOylation of protein phosphatase 5 regulates phosphatase activity and substrate release.","authors":"Rebecca A Sager, Sarah J Backe, Diana M Dunn, Jennifer A Heritz, Elham Ahanin, Natela Dushukyan, Barry Panaretou, Gennady Bratslavsky, Mark R Woodford, Dimitra Bourboulia, Mehdi Mollapour","doi":"10.1038/s44319-024-00250-2","DOIUrl":"10.1038/s44319-024-00250-2","url":null,"abstract":"<p><p>The serine/threonine protein phosphatase 5 (PP5) regulates hormone and stress-induced signaling networks. Unlike other phosphoprotein phosphatases, PP5 contains both regulatory and catalytic domains and is further regulated through post-translational modifications (PTMs). Here we identify that SUMOylation of K430 in the catalytic domain of PP5 regulates phosphatase activity. Additionally, phosphorylation of PP5-T362 is pre-requisite for SUMOylation, suggesting the ordered addition of PTMs regulates PP5 function in cells. Using the glucocorticoid receptor, a well known substrate for PP5, we demonstrate that SUMOylation results in substrate release from PP5. We harness this information to create a non-SUMOylatable K430R mutant as a 'substrate trap' and globally identified novel PP5 substrate candidates. Lastly, we generated a consensus dephosphorylation motif using known substrates, and verified its presence in the new candidate substrates. This study unravels the impact of cross talk of SUMOylation and phosphorylation on PP5 phosphatase activity and substrate release in cells.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"4636-4654"},"PeriodicalIF":6.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549447/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282184","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}
Glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells is a principal mechanism for systemic glucose homeostasis, of which regulatory mechanisms are still unclear. Here we show that kinesin molecular motor KIF5B is essential for GSIS through maintaining the voltage-gated calcium channel CaV1.2 levels, by facilitating an Hsp70-to-Hsp90 chaperone exchange to pass through the quality control in the endoplasmic reticulum (ER). Phenotypic analyses of KIF5B conditional knockout (cKO) mouse beta cells revealed significant abolishment of glucose-stimulated calcium transients, which altered the behaviors of insulin granules via abnormally stabilized cortical F-actin. KIF5B and Hsp90 colocalize to microdroplets on ER sheets, where CaV1.2 but not Kir6.2 is accumulated. In the absence of KIF5B, CaV1.2 fails to be transferred from Hsp70 to Hsp90 via STIP1, and is likely degraded via the proteasomal pathway. KIF5B and Hsc70 overexpression increased CaV1.2 expression via enhancing its chaperone binding. Thus, ER sheets may serve as the place of KIF5B- and Hsp90-dependent chaperone exchange, which predominantly facilitates CaV1.2 production in beta cells and properly enterprises GSIS against diabetes.
{"title":"Kinesin-1 mediates proper ER folding of the Ca<sub>V</sub>1.2 channel and maintains mouse glucose homeostasis.","authors":"Yosuke Tanaka, Atena Farkhondeh, Wenxing Yang, Hitoshi Ueno, Mitsuhiko Noda, Nobutaka Hirokawa","doi":"10.1038/s44319-024-00246-y","DOIUrl":"10.1038/s44319-024-00246-y","url":null,"abstract":"<p><p>Glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells is a principal mechanism for systemic glucose homeostasis, of which regulatory mechanisms are still unclear. Here we show that kinesin molecular motor KIF5B is essential for GSIS through maintaining the voltage-gated calcium channel Ca<sub>V</sub>1.2 levels, by facilitating an Hsp70-to-Hsp90 chaperone exchange to pass through the quality control in the endoplasmic reticulum (ER). Phenotypic analyses of KIF5B conditional knockout (cKO) mouse beta cells revealed significant abolishment of glucose-stimulated calcium transients, which altered the behaviors of insulin granules via abnormally stabilized cortical F-actin. KIF5B and Hsp90 colocalize to microdroplets on ER sheets, where Ca<sub>V</sub>1.2 but not K<sub>ir</sub>6.2 is accumulated. In the absence of KIF5B, Ca<sub>V</sub>1.2 fails to be transferred from Hsp70 to Hsp90 via STIP1, and is likely degraded via the proteasomal pathway. KIF5B and Hsc70 overexpression increased Ca<sub>V</sub>1.2 expression via enhancing its chaperone binding. Thus, ER sheets may serve as the place of KIF5B- and Hsp90-dependent chaperone exchange, which predominantly facilitates Ca<sub>V</sub>1.2 production in beta cells and properly enterprises GSIS against diabetes.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"4777-4802"},"PeriodicalIF":6.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549326/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343799","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 : 2024-11-01Epub Date: 2024-09-24DOI: 10.1038/s44319-024-00274-8
Svenja Ulferts, Robert Grosse
The nucleoskeleton is essential for nuclear architecture as well as genome integrity and gene expression. In addition to lamins, titin or spectrins, dynamic actin filament polymerization has emerged as a potential intranuclear structural element but its functions are less well explored. Here we found that calcium elevations trigger rapid nuclear actin assembly requiring the nuclear membrane protein SUN2 independently of its function as a component of the LINC complex. Instead, SUN2 colocalized and associated with the formin and actin nucleator INF2 in the nuclear envelope in a calcium-regulated manner. Moreover, SUN2 is required for active RNA polymerase II (RNA Pol II) clustering in response to calcium elevations. Thus, our data uncover a SUN2-formin module linking the nuclear envelope to intranuclear actin assembly to promote signal-dependent spatial reorganization of active RNA Pol II.
核骨架对核结构、基因组完整性和基因表达至关重要。除了片蛋白、钛蛋白或光谱蛋白外,动态肌动蛋白丝聚合也已成为一种潜在的核内结构元素,但对其功能的探索还较少。在这里,我们发现钙离子升高会触发核肌动蛋白的快速组装,这需要核膜蛋白 SUN2,而不依赖于它作为 LINC 复合物成分的功能。相反,SUN2 以一种钙调控的方式与核包膜中的形蛋白和肌动蛋白成核因子 INF2 共同定位和关联。此外,SUN2 也是活性 RNA 聚合酶 II(RNA Pol II)在钙离子升高时聚集所必需的。因此,我们的数据揭示了连接核膜与核内肌动蛋白组装的 SUN2-formin模块,以促进活性 RNA Pol II 的信号依赖性空间重组。
{"title":"SUN2 mediates calcium-triggered nuclear actin polymerization to cluster active RNA polymerase II.","authors":"Svenja Ulferts, Robert Grosse","doi":"10.1038/s44319-024-00274-8","DOIUrl":"10.1038/s44319-024-00274-8","url":null,"abstract":"<p><p>The nucleoskeleton is essential for nuclear architecture as well as genome integrity and gene expression. In addition to lamins, titin or spectrins, dynamic actin filament polymerization has emerged as a potential intranuclear structural element but its functions are less well explored. Here we found that calcium elevations trigger rapid nuclear actin assembly requiring the nuclear membrane protein SUN2 independently of its function as a component of the LINC complex. Instead, SUN2 colocalized and associated with the formin and actin nucleator INF2 in the nuclear envelope in a calcium-regulated manner. Moreover, SUN2 is required for active RNA polymerase II (RNA Pol II) clustering in response to calcium elevations. Thus, our data uncover a SUN2-formin module linking the nuclear envelope to intranuclear actin assembly to promote signal-dependent spatial reorganization of active RNA Pol II.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"4728-4748"},"PeriodicalIF":6.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549082/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343801","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 : 2024-11-01Epub Date: 2024-10-02DOI: 10.1038/s44319-024-00249-9
Valentina Taglietti, Kaouthar Kefi, Busra Mirciloglu, Sultan Bastu, Jean-Daniel Masson, Iwona Bronisz-Budzyńska, Vassiliki Gouni, Carlotta Ferri, Alan Jorge, Christel Gentil, France Pietri-Rouxel, Edoardo Malfatti, Peggy Lafuste, Laurent Tiret, Frederic Relaix
Becker muscular dystrophy (BMD) is an X-linked disorder due to in-frame mutations in the DMD gene, leading to a less abundant and truncated dystrophin. BMD is less common and severe than Duchenne muscular dystrophy (DMD) as well as less investigated. To accelerate the search for innovative treatments, we developed a rat model of BMD by deleting the exons 45-47 of the Dmd gene. Here, we report a functional and histopathological evaluation of these rats during their first year of life, compared to DMD and control littermates. BMD rats exhibit moderate damage to locomotor and diaphragmatic muscles but suffer from a progressive cardiomyopathy. Single nuclei RNA-seq analysis of cardiac samples revealed shared transcriptomic abnormalities in BMD and DMD rats and highlighted an altered end-addressing of TMEM65 and Connexin-43 at the intercalated disc, along with electrocardiographic abnormalities. Our study documents the natural history of a translational preclinical model of BMD and reports a cellular mechanism for the cardiac dysfunction in BMD and DMD offering opportunities to further investigate the organization role of dystrophin in intercellular communication.
{"title":"Progressive cardiomyopathy with intercalated disc disorganization in a rat model of Becker dystrophy.","authors":"Valentina Taglietti, Kaouthar Kefi, Busra Mirciloglu, Sultan Bastu, Jean-Daniel Masson, Iwona Bronisz-Budzyńska, Vassiliki Gouni, Carlotta Ferri, Alan Jorge, Christel Gentil, France Pietri-Rouxel, Edoardo Malfatti, Peggy Lafuste, Laurent Tiret, Frederic Relaix","doi":"10.1038/s44319-024-00249-9","DOIUrl":"10.1038/s44319-024-00249-9","url":null,"abstract":"<p><p>Becker muscular dystrophy (BMD) is an X-linked disorder due to in-frame mutations in the DMD gene, leading to a less abundant and truncated dystrophin. BMD is less common and severe than Duchenne muscular dystrophy (DMD) as well as less investigated. To accelerate the search for innovative treatments, we developed a rat model of BMD by deleting the exons 45-47 of the Dmd gene. Here, we report a functional and histopathological evaluation of these rats during their first year of life, compared to DMD and control littermates. BMD rats exhibit moderate damage to locomotor and diaphragmatic muscles but suffer from a progressive cardiomyopathy. Single nuclei RNA-seq analysis of cardiac samples revealed shared transcriptomic abnormalities in BMD and DMD rats and highlighted an altered end-addressing of TMEM65 and Connexin-43 at the intercalated disc, along with electrocardiographic abnormalities. Our study documents the natural history of a translational preclinical model of BMD and reports a cellular mechanism for the cardiac dysfunction in BMD and DMD offering opportunities to further investigate the organization role of dystrophin in intercellular communication.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"4898-4920"},"PeriodicalIF":6.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364832","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 : 2024-11-01Epub Date: 2024-10-11DOI: 10.1038/s44319-024-00283-7
Anika Pupak, Irene Rodríguez-Navarro, Kirupa Sathasivam, Ankita Singh, Amelie Essmann, Daniel Del Toro, Silvia Ginés, Ricardo Mouro Pinto, Gillian P Bates, Ulf Andersson Vang Ørom, Eulàlia Martí, Verónica Brito
In Huntington's disease (HD), aberrant processing of huntingtin (HTT) mRNA produces HTT1a transcripts that encode the pathogenic HTT exon 1 protein. The mechanisms behind HTT1a production are not fully understood. Considering the role of m6A in RNA processing and splicing, we investigated its involvement in HTT1a generation. Here, we show that m6A methylation is increased before the cryptic poly(A) sites (IpA1 and IpA2) within the huntingtin RNA in the striatum of Hdh+/Q111 mice and human HD samples. We further assessed m6A's role in mutant Htt mRNA processing by pharmacological inhibition and knockdown of METTL3, as well as targeted demethylation of Htt intron 1 using a dCas13-ALKBH5 system in HD mouse cells. Our data reveal that Htt1a transcript levels are regulated by both METTL3 and the methylation status of Htt intron 1. They also show that m6A methylation in intron 1 depends on expanded CAG repeats. Our findings highlight a potential role for m6A in aberrant splicing of Htt mRNA.
{"title":"m<sup>6</sup>A modification of mutant huntingtin RNA promotes the biogenesis of pathogenic huntingtin transcripts.","authors":"Anika Pupak, Irene Rodríguez-Navarro, Kirupa Sathasivam, Ankita Singh, Amelie Essmann, Daniel Del Toro, Silvia Ginés, Ricardo Mouro Pinto, Gillian P Bates, Ulf Andersson Vang Ørom, Eulàlia Martí, Verónica Brito","doi":"10.1038/s44319-024-00283-7","DOIUrl":"10.1038/s44319-024-00283-7","url":null,"abstract":"<p><p>In Huntington's disease (HD), aberrant processing of huntingtin (HTT) mRNA produces HTT1a transcripts that encode the pathogenic HTT exon 1 protein. The mechanisms behind HTT1a production are not fully understood. Considering the role of m<sup>6</sup>A in RNA processing and splicing, we investigated its involvement in HTT1a generation. Here, we show that m<sup>6</sup>A methylation is increased before the cryptic poly(A) sites (IpA1 and IpA2) within the huntingtin RNA in the striatum of Hdh+/Q111 mice and human HD samples. We further assessed m<sup>6</sup>A's role in mutant Htt mRNA processing by pharmacological inhibition and knockdown of METTL3, as well as targeted demethylation of Htt intron 1 using a dCas13-ALKBH5 system in HD mouse cells. Our data reveal that Htt1a transcript levels are regulated by both METTL3 and the methylation status of Htt intron 1. They also show that m<sup>6</sup>A methylation in intron 1 depends on expanded CAG repeats. Our findings highlight a potential role for m<sup>6</sup>A in aberrant splicing of Htt mRNA.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"5026-5052"},"PeriodicalIF":6.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406238","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 : 2024-11-01Epub Date: 2024-09-27DOI: 10.1038/s44319-024-00276-6
Jiangyun Shen, Liyan Lou, Xue Du, Bincheng Zhou, Yanqi Xu, Fuqi Mei, Liangrong Wu, Jianmin Li, Ari Waisman, Jing Ruan, Xu Wang
Inflammatory bowel disease (IBD) is a disorder causing chronic inflammation in the gastrointestinal tract, and its pathophysiological mechanisms are still under investigation. Here, we find that mice deficient of YOD1, a deubiquitinating enzyme, are highly susceptible to dextran sulfate sodium (DSS)-induced colitis. The bone marrow transplantation experiment reveals that YOD1 derived from hematopoietic cells inhibits DSS colitis. Moreover, YOD1 exerts its protective role by promoting nucleotide-binding oligomerization domain 2 (NOD2)-mediated physiological inflammation in macrophages. Mechanistically, YOD1 inhibits the proteasomal degradation of receptor-interacting serine/threonine kinase 2 (RIPK2) by reducing its K48 polyubiquitination, thereby increasing RIPK2 abundance to enhance NOD2 signaling. Consistently, the protective function of muramyldipeptide, a NOD2 ligand, in experimental colitis is abolished in mice deficient of YOD1. Importantly, YOD1 is upregulated in colon-infiltrating macrophages in patients with colitis. Collectively, this study identifies YOD1 as a novel regulator of colitis.
{"title":"YOD1 sustains NOD2-mediated protective signaling in colitis by stabilizing RIPK2.","authors":"Jiangyun Shen, Liyan Lou, Xue Du, Bincheng Zhou, Yanqi Xu, Fuqi Mei, Liangrong Wu, Jianmin Li, Ari Waisman, Jing Ruan, Xu Wang","doi":"10.1038/s44319-024-00276-6","DOIUrl":"10.1038/s44319-024-00276-6","url":null,"abstract":"<p><p>Inflammatory bowel disease (IBD) is a disorder causing chronic inflammation in the gastrointestinal tract, and its pathophysiological mechanisms are still under investigation. Here, we find that mice deficient of YOD1, a deubiquitinating enzyme, are highly susceptible to dextran sulfate sodium (DSS)-induced colitis. The bone marrow transplantation experiment reveals that YOD1 derived from hematopoietic cells inhibits DSS colitis. Moreover, YOD1 exerts its protective role by promoting nucleotide-binding oligomerization domain 2 (NOD2)-mediated physiological inflammation in macrophages. Mechanistically, YOD1 inhibits the proteasomal degradation of receptor-interacting serine/threonine kinase 2 (RIPK2) by reducing its K48 polyubiquitination, thereby increasing RIPK2 abundance to enhance NOD2 signaling. Consistently, the protective function of muramyldipeptide, a NOD2 ligand, in experimental colitis is abolished in mice deficient of YOD1. Importantly, YOD1 is upregulated in colon-infiltrating macrophages in patients with colitis. Collectively, this study identifies YOD1 as a novel regulator of colitis.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"4827-4845"},"PeriodicalIF":6.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549337/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343804","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 : 2024-11-01Epub Date: 2024-10-10DOI: 10.1038/s44319-024-00284-6
Maxime Libert, Sophie Quiquempoix, Jean S Fain, Sébastien Pyr Dit Ruys, Malak Haidar, Margaux Wulleman, Gaëtan Herinckx, Didier Vertommen, Christelle Bouchart, Tatjana Arsenijevic, Jean-Luc Van Laethem, Patrick Jacquemin
Stress granules (SG) are membraneless ribonucleoprotein-based cytoplasmic organelles that assemble in response to stress. Their formation is often associated with an almost global suppression of translation, and the aberrant assembly or disassembly of these granules has pathological implications in neurodegeneration and cancer. In cancer, and particularly in the presence of oncogenic KRAS mutations, in vivo studies concluded that SG increase the resistance of cancer cells to stress. Hence, SG have recently been considered a promising target for therapy. Here, starting from our observations that genes coding for SG proteins are stimulated during development of pancreatic ductal adenocarcinoma, we analyze the formation of SG during tumorigenesis. We resort to in vitro, in vivo and in silico approaches, using mouse models, human samples and human data. Our analyses do not support that SG are formed during tumorigenesis of KRAS-driven cancers, at least that their presence is not universal, leading us to propose that caution is required before considering SG as therapeutic targets.
{"title":"Stress granules are not present in Kras mutant cancers and do not control tumor growth.","authors":"Maxime Libert, Sophie Quiquempoix, Jean S Fain, Sébastien Pyr Dit Ruys, Malak Haidar, Margaux Wulleman, Gaëtan Herinckx, Didier Vertommen, Christelle Bouchart, Tatjana Arsenijevic, Jean-Luc Van Laethem, Patrick Jacquemin","doi":"10.1038/s44319-024-00284-6","DOIUrl":"10.1038/s44319-024-00284-6","url":null,"abstract":"<p><p>Stress granules (SG) are membraneless ribonucleoprotein-based cytoplasmic organelles that assemble in response to stress. Their formation is often associated with an almost global suppression of translation, and the aberrant assembly or disassembly of these granules has pathological implications in neurodegeneration and cancer. In cancer, and particularly in the presence of oncogenic KRAS mutations, in vivo studies concluded that SG increase the resistance of cancer cells to stress. Hence, SG have recently been considered a promising target for therapy. Here, starting from our observations that genes coding for SG proteins are stimulated during development of pancreatic ductal adenocarcinoma, we analyze the formation of SG during tumorigenesis. We resort to in vitro, in vivo and in silico approaches, using mouse models, human samples and human data. Our analyses do not support that SG are formed during tumorigenesis of KRAS-driven cancers, at least that their presence is not universal, leading us to propose that caution is required before considering SG as therapeutic targets.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"4693-4707"},"PeriodicalIF":6.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549491/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399762","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 : 2024-11-01Epub Date: 2024-10-02DOI: 10.1038/s44319-024-00272-w
Gyan Ranjan, Paras Sehgal, Vinod Scaria, Sridhar Sivasubbu
In this study, we characterize a novel lncRNA-producing gene locus that we name Syntenic Cardiovascular Conserved Region-Associated lncRNA-6 (scar-6) and functionally validate its role in coagulation and cardiovascular function. A 12-bp deletion of the scar-6 locus in zebrafish (scar-6gib007Δ12/Δ12) results in cranial hemorrhage and vascular permeability. Overexpression, knockdown and rescue with the scar-6 lncRNA modulates hemostasis in zebrafish. Molecular investigation reveals that the scar-6 lncRNA acts as an enhancer lncRNA (elncRNA), and controls the expression of prozb, an inhibitor of factor Xa, through an enhancer element in the scar-6 locus. The scar-6 locus suppresses loop formation between prozb and scar-6 sequences, which might be facilitated by the methylation of CpG islands via the prdm14-PRC2 complex whose binding to the locus might be stabilized by the scar-6 elncRNA transcript. Binding of prdm14 to the scar-6 locus is impaired in scar-6gib007Δ12/Δ12 zebrafish. Finally, activation of the PAR2 receptor in scar-6gib007Δ12/Δ12 zebrafish triggers NF-κB-mediated endothelial cell activation, leading to vascular dysfunction and hemorrhage. We present evidence that the scar-6 locus plays a role in regulating the expression of the coagulation cascade gene prozb and maintains vascular homeostasis.
{"title":"SCAR-6 elncRNA locus epigenetically regulates PROZ and modulates coagulation and vascular function.","authors":"Gyan Ranjan, Paras Sehgal, Vinod Scaria, Sridhar Sivasubbu","doi":"10.1038/s44319-024-00272-w","DOIUrl":"10.1038/s44319-024-00272-w","url":null,"abstract":"<p><p>In this study, we characterize a novel lncRNA-producing gene locus that we name Syntenic Cardiovascular Conserved Region-Associated lncRNA-6 (scar-6) and functionally validate its role in coagulation and cardiovascular function. A 12-bp deletion of the scar-6 locus in zebrafish (scar-6<sup>gib007Δ12/Δ12</sup>) results in cranial hemorrhage and vascular permeability. Overexpression, knockdown and rescue with the scar-6 lncRNA modulates hemostasis in zebrafish. Molecular investigation reveals that the scar-6 lncRNA acts as an enhancer lncRNA (elncRNA), and controls the expression of prozb, an inhibitor of factor Xa, through an enhancer element in the scar-6 locus. The scar-6 locus suppresses loop formation between prozb and scar-6 sequences, which might be facilitated by the methylation of CpG islands via the prdm14-PRC2 complex whose binding to the locus might be stabilized by the scar-6 elncRNA transcript. Binding of prdm14 to the scar-6 locus is impaired in scar-6<sup>gib007Δ12/Δ12</sup> zebrafish. Finally, activation of the PAR2 receptor in scar-6<sup>gib007Δ12/Δ12</sup> zebrafish triggers NF-κB-mediated endothelial cell activation, leading to vascular dysfunction and hemorrhage. We present evidence that the scar-6 locus plays a role in regulating the expression of the coagulation cascade gene prozb and maintains vascular homeostasis.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"4950-4978"},"PeriodicalIF":6.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549340/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364833","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}