Muhammad Zahoor, Yanchen Dong, Marco Preussner, Veronika Reiterer, Sabrina Shameen Alam, Margot Haun, Utku Horzum, Yannick Frey, Renata Hajdu, Stephan Geley, Valerie Cormier-Daire, Florian Heyd, Loydie A Jerome-Majewska, Hesso Farhan
{"title":"未折叠蛋白反应通过 SNRPB 依赖性 RNA 剪接调节 ER 出口位点,并促进骨骼发育。","authors":"Muhammad Zahoor, Yanchen Dong, Marco Preussner, Veronika Reiterer, Sabrina Shameen Alam, Margot Haun, Utku Horzum, Yannick Frey, Renata Hajdu, Stephan Geley, Valerie Cormier-Daire, Florian Heyd, Loydie A Jerome-Majewska, Hesso Farhan","doi":"10.1038/s44318-024-00208-z","DOIUrl":null,"url":null,"abstract":"<p><p>Splicing and endoplasmic reticulum (ER)-proteostasis are two key processes that ultimately regulate the functional proteins that are produced by a cell. However, the extent to which these processes interact remains poorly understood. Here, we identify SNRPB and other components of the Sm-ring, as targets of the unfolded protein response and novel regulators of export from the ER. Mechanistically, The Sm-ring regulates the splicing of components of the ER export machinery, including Sec16A, a component of ER exit sites. Loss of function of SNRPB is causally linked to cerebro-costo-mandibular syndrome (CCMS), a genetic disease characterized by bone defects. We show that heterozygous deletion of SNRPB in mice resulted in bone defects reminiscent of CCMS and that knockdown of SNRPB delays the trafficking of type-I collagen. Silencing SNRPB inhibited osteogenesis in vitro, which could be rescued by overexpression of Sec16A. This rescue indicates that the role of SNRPB in osteogenesis is linked to its effects on ER-export. Finally, we show that SNRPB is a target for the unfolded protein response, which supports a mechanistic link between the spliceosome and ER-proteostasis. Our work highlights components of the Sm-ring as a novel node in the proteostasis network, shedding light on CCMS pathophysiology.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":null,"pages":null},"PeriodicalIF":9.4000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11445528/pdf/","citationCount":"0","resultStr":"{\"title\":\"The unfolded protein response regulates ER exit sites via SNRPB-dependent RNA splicing and contributes to bone development.\",\"authors\":\"Muhammad Zahoor, Yanchen Dong, Marco Preussner, Veronika Reiterer, Sabrina Shameen Alam, Margot Haun, Utku Horzum, Yannick Frey, Renata Hajdu, Stephan Geley, Valerie Cormier-Daire, Florian Heyd, Loydie A Jerome-Majewska, Hesso Farhan\",\"doi\":\"10.1038/s44318-024-00208-z\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Splicing and endoplasmic reticulum (ER)-proteostasis are two key processes that ultimately regulate the functional proteins that are produced by a cell. However, the extent to which these processes interact remains poorly understood. Here, we identify SNRPB and other components of the Sm-ring, as targets of the unfolded protein response and novel regulators of export from the ER. Mechanistically, The Sm-ring regulates the splicing of components of the ER export machinery, including Sec16A, a component of ER exit sites. Loss of function of SNRPB is causally linked to cerebro-costo-mandibular syndrome (CCMS), a genetic disease characterized by bone defects. We show that heterozygous deletion of SNRPB in mice resulted in bone defects reminiscent of CCMS and that knockdown of SNRPB delays the trafficking of type-I collagen. Silencing SNRPB inhibited osteogenesis in vitro, which could be rescued by overexpression of Sec16A. This rescue indicates that the role of SNRPB in osteogenesis is linked to its effects on ER-export. Finally, we show that SNRPB is a target for the unfolded protein response, which supports a mechanistic link between the spliceosome and ER-proteostasis. Our work highlights components of the Sm-ring as a novel node in the proteostasis network, shedding light on CCMS pathophysiology.</p>\",\"PeriodicalId\":50533,\"journal\":{\"name\":\"EMBO Journal\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":9.4000,\"publicationDate\":\"2024-10-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11445528/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"EMBO Journal\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1038/s44318-024-00208-z\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/8/19 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"EMBO Journal","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s44318-024-00208-z","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/8/19 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
剪接和内质网(ER)保护稳态是最终调节细胞产生的功能蛋白质的两个关键过程。然而,人们对这两个过程的相互作用程度仍然知之甚少。在这里,我们发现 SNRPB 和 Sm-ring 的其他成分是未折叠蛋白反应的靶标和从 ER 输出的新型调控因子。从机理上讲,Sm-ring调节ER出口机制成分的剪接,包括ER出口位点的一个成分Sec16A。SNRPB的功能缺失与脑肋骨综合征(CCMS)有因果关系,这是一种以骨骼缺陷为特征的遗传病。我们的研究表明,小鼠杂合性缺失 SNRPB 会导致类似 CCMS 的骨骼缺陷,而且敲除 SNRPB 会延迟 I 型胶原蛋白的贩运。沉默SNRPB会抑制体外成骨,而过表达Sec16A可以挽救这种抑制。这种拯救表明,SNRPB 在成骨过程中的作用与其对 ER 出口的影响有关。最后,我们发现 SNRPB 是未折叠蛋白反应的一个靶标,这支持了剪接体与 ER 蛋白稳态之间的机理联系。我们的研究突出了作为蛋白稳态网络中一个新节点的Sm环的组成成分,为CCMS病理生理学提供了启示。
The unfolded protein response regulates ER exit sites via SNRPB-dependent RNA splicing and contributes to bone development.
Splicing and endoplasmic reticulum (ER)-proteostasis are two key processes that ultimately regulate the functional proteins that are produced by a cell. However, the extent to which these processes interact remains poorly understood. Here, we identify SNRPB and other components of the Sm-ring, as targets of the unfolded protein response and novel regulators of export from the ER. Mechanistically, The Sm-ring regulates the splicing of components of the ER export machinery, including Sec16A, a component of ER exit sites. Loss of function of SNRPB is causally linked to cerebro-costo-mandibular syndrome (CCMS), a genetic disease characterized by bone defects. We show that heterozygous deletion of SNRPB in mice resulted in bone defects reminiscent of CCMS and that knockdown of SNRPB delays the trafficking of type-I collagen. Silencing SNRPB inhibited osteogenesis in vitro, which could be rescued by overexpression of Sec16A. This rescue indicates that the role of SNRPB in osteogenesis is linked to its effects on ER-export. Finally, we show that SNRPB is a target for the unfolded protein response, which supports a mechanistic link between the spliceosome and ER-proteostasis. Our work highlights components of the Sm-ring as a novel node in the proteostasis network, shedding light on CCMS pathophysiology.
期刊介绍:
The EMBO Journal has stood as EMBO's flagship publication since its inception in 1982. Renowned for its international reputation in quality and originality, the journal spans all facets of molecular biology. It serves as a platform for papers elucidating original research of broad general interest in molecular and cell biology, with a distinct focus on molecular mechanisms and physiological relevance.
With a commitment to promoting articles reporting novel findings of broad biological significance, The EMBO Journal stands as a key contributor to advancing the field of molecular biology.