Pub Date : 2024-10-03DOI: 10.1038/s44318-024-00256-5
Shashank K Pandey, Jay Prakash Maurya, Bibek Aryal, Kamil Drynda, Aswin Nair, Pal Miskolczi, Rajesh Kumar Singh, Xiaobin Wang, Yujiao Ma, Tatiana de Souza Moraes, Emmanuelle M Bayer, Etienne Farcot, George W Bassel, Leah R Band, Rishikesh P Bhalerao
The control of cell-cell communication via plasmodesmata (PD) plays a key role in plant development. In tree buds, low-temperature conditions (LT) induce a switch in plasmodesmata from a closed to an open state, which restores cell-to-cell communication in the shoot apex and releases dormancy. Using genetic and cell-biological approaches, we have identified a previously uncharacterized transcription factor, Low-temperature-Induced MADS-box 1 (LIM1), as an LT-induced, direct upstream activator of the gibberellic acid (GA) pathway. The LIM1-GA module mediates low temperature-induced plasmodesmata opening, by negatively regulating callose accumulation to promote dormancy release. LIM1 also activates expression of FT1 (FLOWERING LOCUS T), another LT-induced factor, with LIM1-FT1 forming a coherent feedforward loop converging on low-temperature regulation of gibberellin signaling in dormancy release. Mathematical modeling and experimental validation suggest that negative feedback regulation of LIM1 by gibberellin could play a crucial role in maintaining the robust temporal regulation of bud responses to low temperature. These results reveal genetic factors linking temperature control of cell-cell communication with regulation of seasonally-aligned growth crucial for adaptation of trees.
{"title":"A regulatory module mediating temperature control of cell-cell communication facilitates tree bud dormancy release.","authors":"Shashank K Pandey, Jay Prakash Maurya, Bibek Aryal, Kamil Drynda, Aswin Nair, Pal Miskolczi, Rajesh Kumar Singh, Xiaobin Wang, Yujiao Ma, Tatiana de Souza Moraes, Emmanuelle M Bayer, Etienne Farcot, George W Bassel, Leah R Band, Rishikesh P Bhalerao","doi":"10.1038/s44318-024-00256-5","DOIUrl":"https://doi.org/10.1038/s44318-024-00256-5","url":null,"abstract":"<p><p>The control of cell-cell communication via plasmodesmata (PD) plays a key role in plant development. In tree buds, low-temperature conditions (LT) induce a switch in plasmodesmata from a closed to an open state, which restores cell-to-cell communication in the shoot apex and releases dormancy. Using genetic and cell-biological approaches, we have identified a previously uncharacterized transcription factor, Low-temperature-Induced MADS-box 1 (LIM1), as an LT-induced, direct upstream activator of the gibberellic acid (GA) pathway. The LIM1-GA module mediates low temperature-induced plasmodesmata opening, by negatively regulating callose accumulation to promote dormancy release. LIM1 also activates expression of FT1 (FLOWERING LOCUS T), another LT-induced factor, with LIM1-FT1 forming a coherent feedforward loop converging on low-temperature regulation of gibberellin signaling in dormancy release. Mathematical modeling and experimental validation suggest that negative feedback regulation of LIM1 by gibberellin could play a crucial role in maintaining the robust temporal regulation of bud responses to low temperature. These results reveal genetic factors linking temperature control of cell-cell communication with regulation of seasonally-aligned growth crucial for adaptation of trees.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142373453","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 : 2024-10-02DOI: 10.1038/s44318-024-00257-4
Yang Tang, Fan Chen, Gemin Fang, Hui Zhang, Yanni Zhang, Hanying Zhu, Xinru Zhang, Yi Han, Zhifa Cao, Fenghua Guo, Wenjia Wang, Dan Ye, Junyi Ju, Lijie Tan, Chuanchuan Li, Yun Zhao, Zhaocai Zhou, Liwei An, Shi Jiao
Transcriptional factors (TFs) act as key determinants of cell death and survival by differentially modulating gene expression. Here, we identified many TFs, including TEAD4, that form condensates in stressed cells. In contrast to YAP-induced transcription-activating condensates of TEAD4, we found that co-factors such as VGLL4 and RFXANK alternatively induced repressive TEAD4 condensates to trigger cell death upon glucose starvation. Focusing on VGLL4, we demonstrated that heterotypic interactions between TEAD4 and VGLL4 favor the oligomerization and assembly of large TEAD4 condensates with a nonclassical inhibitory function, i.e., causing DNA/chromatin to be aggregated and entangled, which eventually impede gene expression. Based on these findings, we engineered a peptide derived from the TEAD4-binding motif of VGLL4 to selectively induce TEAD4 repressive condensation. This "glue" peptide displayed a strong antitumor effect in genetic and xenograft mouse models of gastric cancer via inhibition of TEAD4-related gene transcription. This new type of repressive TF phase separation exemplifies how cofactors can orchestrate opposite functions of a given TF, and offers potential new antitumor strategies via artificial induction of repressive condensation.
{"title":"A cofactor-induced repressive type of transcription factor condensation can be induced by synthetic peptides to suppress tumorigenesis.","authors":"Yang Tang, Fan Chen, Gemin Fang, Hui Zhang, Yanni Zhang, Hanying Zhu, Xinru Zhang, Yi Han, Zhifa Cao, Fenghua Guo, Wenjia Wang, Dan Ye, Junyi Ju, Lijie Tan, Chuanchuan Li, Yun Zhao, Zhaocai Zhou, Liwei An, Shi Jiao","doi":"10.1038/s44318-024-00257-4","DOIUrl":"https://doi.org/10.1038/s44318-024-00257-4","url":null,"abstract":"<p><p>Transcriptional factors (TFs) act as key determinants of cell death and survival by differentially modulating gene expression. Here, we identified many TFs, including TEAD4, that form condensates in stressed cells. In contrast to YAP-induced transcription-activating condensates of TEAD4, we found that co-factors such as VGLL4 and RFXANK alternatively induced repressive TEAD4 condensates to trigger cell death upon glucose starvation. Focusing on VGLL4, we demonstrated that heterotypic interactions between TEAD4 and VGLL4 favor the oligomerization and assembly of large TEAD4 condensates with a nonclassical inhibitory function, i.e., causing DNA/chromatin to be aggregated and entangled, which eventually impede gene expression. Based on these findings, we engineered a peptide derived from the TEAD4-binding motif of VGLL4 to selectively induce TEAD4 repressive condensation. This \"glue\" peptide displayed a strong antitumor effect in genetic and xenograft mouse models of gastric cancer via inhibition of TEAD4-related gene transcription. This new type of repressive TF phase separation exemplifies how cofactors can orchestrate opposite functions of a given TF, and offers potential new antitumor strategies via artificial induction of repressive condensation.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142367292","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 : 2024-10-01Epub Date: 2024-08-27DOI: 10.1038/s44318-024-00199-x
James A Spudich, Neha Nandwani, Julien Robert-Paganin, Anne Houdusse, Kathleen M Ruppel
{"title":"Reassessing the unifying hypothesis for hypercontractility caused by myosin mutations in hypertrophic cardiomyopathy.","authors":"James A Spudich, Neha Nandwani, Julien Robert-Paganin, Anne Houdusse, Kathleen M Ruppel","doi":"10.1038/s44318-024-00199-x","DOIUrl":"10.1038/s44318-024-00199-x","url":null,"abstract":"","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11445530/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142082461","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 : 2024-10-01Epub Date: 2024-08-19DOI: 10.1038/s44318-024-00189-z
Elizabeth Lieschke, Annabella F Thomas, Andrew Kueh, Georgia K Atkin-Smith, Pedro L Baldoni, John E La Marca, Savannah Young, Allan Shuai Huang, Aisling M Ross, Lauren Whelan, Deeksha Kaloni, Lin Tai, Gordon K Smyth, Marco J Herold, Edwin D Hawkins, Andreas Strasser, Gemma L Kelly
Investigating how transcription factors control complex cellular processes requires tools that enable responses to be visualised at the single-cell level and their cell fate to be followed over time. For example, the tumour suppressor p53 (also called TP53 in humans and TRP53 in mice) can initiate diverse cellular responses by transcriptional activation of its target genes: Puma to induce apoptotic cell death and p21 to induce cell cycle arrest/cell senescence. However, it is not known how these processes are regulated and initiated in different cell types. Also, the context-dependent interaction partners and binding loci of p53 remain largely elusive. To be able to examine these questions, we here developed knock-in mice expressing triple-FLAG-tagged p53 to facilitate p53 pull-down and two p53 response reporter mice, knocking tdTomato and GFP into the Puma/Bbc3 and p21 gene loci, respectively. By crossing these reporter mice into a p53-deficient background, we show that the new reporters reliably inform on p53-dependent and p53-independent initiation of both apoptotic or cell cycle arrest/senescence programs, respectively, in vitro and in vivo.
{"title":"Mouse models to investigate in situ cell fate decisions induced by p53.","authors":"Elizabeth Lieschke, Annabella F Thomas, Andrew Kueh, Georgia K Atkin-Smith, Pedro L Baldoni, John E La Marca, Savannah Young, Allan Shuai Huang, Aisling M Ross, Lauren Whelan, Deeksha Kaloni, Lin Tai, Gordon K Smyth, Marco J Herold, Edwin D Hawkins, Andreas Strasser, Gemma L Kelly","doi":"10.1038/s44318-024-00189-z","DOIUrl":"10.1038/s44318-024-00189-z","url":null,"abstract":"<p><p>Investigating how transcription factors control complex cellular processes requires tools that enable responses to be visualised at the single-cell level and their cell fate to be followed over time. For example, the tumour suppressor p53 (also called TP53 in humans and TRP53 in mice) can initiate diverse cellular responses by transcriptional activation of its target genes: Puma to induce apoptotic cell death and p21 to induce cell cycle arrest/cell senescence. However, it is not known how these processes are regulated and initiated in different cell types. Also, the context-dependent interaction partners and binding loci of p53 remain largely elusive. To be able to examine these questions, we here developed knock-in mice expressing triple-FLAG-tagged p53 to facilitate p53 pull-down and two p53 response reporter mice, knocking tdTomato and GFP into the Puma/Bbc3 and p21 gene loci, respectively. By crossing these reporter mice into a p53-deficient background, we show that the new reporters reliably inform on p53-dependent and p53-independent initiation of both apoptotic or cell cycle arrest/senescence programs, respectively, in vitro and in vivo.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11445477/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142005776","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}
Multimeric membrane proteins are produced in the endoplasmic reticulum and transported to their target membranes which, for ion channels, is typically the plasma membrane. Despite the availability of many fully assembled channel structures, our understanding of assembly intermediates, multimer assembly mechanisms, and potential functions of non-standard assemblies is limited. We demonstrate that the pentameric ligand-gated serotonin 5-HT3A receptor (5-HT3AR) can assemble to tetrameric forms and report the structures of the tetramers in plasma membranes of cell-derived microvesicles and in membrane memetics using cryo-electron microscopy and tomography. The tetrameric structures have near-symmetric transmembrane domains, and asymmetric extracellular domains, and can bind serotonin molecules. Computer simulations, based on our cryo-EM structures, were used to decipher the assembly pathway of pentameric 5-HT3R and suggest a potential functional role for the tetrameric receptors.
{"title":"Structure of tetrameric forms of the serotonin-gated 5-HT3<sub>A</sub> receptor ion channel.","authors":"Bianca Introini, Wenqiang Cui, Xiaofeng Chu, Yingyi Zhang, Ana Catarina Alves, Luise Eckhardt-Strelau, Sabrina Golusik, Menno Tol, Horst Vogel, Shuguang Yuan, Mikhail Kudryashev","doi":"10.1038/s44318-024-00191-5","DOIUrl":"10.1038/s44318-024-00191-5","url":null,"abstract":"<p><p>Multimeric membrane proteins are produced in the endoplasmic reticulum and transported to their target membranes which, for ion channels, is typically the plasma membrane. Despite the availability of many fully assembled channel structures, our understanding of assembly intermediates, multimer assembly mechanisms, and potential functions of non-standard assemblies is limited. We demonstrate that the pentameric ligand-gated serotonin 5-HT3A receptor (5-HT3AR) can assemble to tetrameric forms and report the structures of the tetramers in plasma membranes of cell-derived microvesicles and in membrane memetics using cryo-electron microscopy and tomography. The tetrameric structures have near-symmetric transmembrane domains, and asymmetric extracellular domains, and can bind serotonin molecules. Computer simulations, based on our cryo-EM structures, were used to decipher the assembly pathway of pentameric 5-HT3R and suggest a potential functional role for the tetrameric receptors.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11480441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142134356","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 : 2024-10-01Epub Date: 2024-09-10DOI: 10.1038/s44318-024-00200-7
David Bradley, Alexander Hogrebe, Rohan Dandage, Alexandre K Dubé, Mario Leutert, Ugo Dionne, Alexis Chang, Judit Villén, Christian R Landry
The fidelity of signal transduction requires the binding of regulatory molecules to their cognate targets. However, the crowded cell interior risks off-target interactions between proteins that are functionally unrelated. How such off-target interactions impact fitness is not generally known. Here, we use Saccharomyces cerevisiae to inducibly express tyrosine kinases. Because yeast lacks bona fide tyrosine kinases, the resulting tyrosine phosphorylation is biologically spurious. We engineered 44 yeast strains each expressing a tyrosine kinase, and quantitatively analysed their phosphoproteomes. This analysis resulted in ~30,000 phosphosites mapping to ~3500 proteins. The number of spurious pY sites generated correlates strongly with decreased growth, and we predict over 1000 pY events to be deleterious. However, we also find that many of the spurious pY sites have a negligible effect on fitness, possibly because of their low stoichiometry. This result is consistent with our evolutionary analyses demonstrating a lack of phosphotyrosine counter-selection in species with tyrosine kinases. Our results suggest that, alongside the risk for toxicity, the cell can tolerate a large degree of non-functional crosstalk as interaction networks evolve.
{"title":"The fitness cost of spurious phosphorylation.","authors":"David Bradley, Alexander Hogrebe, Rohan Dandage, Alexandre K Dubé, Mario Leutert, Ugo Dionne, Alexis Chang, Judit Villén, Christian R Landry","doi":"10.1038/s44318-024-00200-7","DOIUrl":"10.1038/s44318-024-00200-7","url":null,"abstract":"<p><p>The fidelity of signal transduction requires the binding of regulatory molecules to their cognate targets. However, the crowded cell interior risks off-target interactions between proteins that are functionally unrelated. How such off-target interactions impact fitness is not generally known. Here, we use Saccharomyces cerevisiae to inducibly express tyrosine kinases. Because yeast lacks bona fide tyrosine kinases, the resulting tyrosine phosphorylation is biologically spurious. We engineered 44 yeast strains each expressing a tyrosine kinase, and quantitatively analysed their phosphoproteomes. This analysis resulted in ~30,000 phosphosites mapping to ~3500 proteins. The number of spurious pY sites generated correlates strongly with decreased growth, and we predict over 1000 pY events to be deleterious. However, we also find that many of the spurious pY sites have a negligible effect on fitness, possibly because of their low stoichiometry. This result is consistent with our evolutionary analyses demonstrating a lack of phosphotyrosine counter-selection in species with tyrosine kinases. Our results suggest that, alongside the risk for toxicity, the cell can tolerate a large degree of non-functional crosstalk as interaction networks evolve.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11480408/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142300040","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 : 2024-10-01DOI: 10.1038/s44318-024-00157-7
Lena Wischhof, Hang-Mao Lee, Janine Tutas, Clemens Overkott, Eileen Tedt, Miriam Stork, Michael Peitz, Oliver Brüstle, Thomas Ulas, Kristian Händler, Joachim L Schultze, Dan Ehninger, Pierluigi Nicotera, Paolo Salomoni, Daniele Bano
{"title":"Author Correction: BCL7A-containing SWI/SNF/BAF complexes modulate mitochondrial bioenergetics during neural progenitor differentiation.","authors":"Lena Wischhof, Hang-Mao Lee, Janine Tutas, Clemens Overkott, Eileen Tedt, Miriam Stork, Michael Peitz, Oliver Brüstle, Thomas Ulas, Kristian Händler, Joachim L Schultze, Dan Ehninger, Pierluigi Nicotera, Paolo Salomoni, Daniele Bano","doi":"10.1038/s44318-024-00157-7","DOIUrl":"10.1038/s44318-024-00157-7","url":null,"abstract":"","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11445569/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142121038","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 : 2024-10-01Epub Date: 2024-08-19DOI: 10.1038/s44318-024-00208-z
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
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.
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。
{"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":"10.1038/s44318-024-00208-z","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":9.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11445528/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142005778","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 : 2024-10-01Epub Date: 2024-08-29DOI: 10.1038/s44318-024-00188-0
Yuliya Kurlishchuk, Anita Cindric Vranesic, Marco Jessen, Alexandra Kipping, Christin Ritter, KyungMok Kim, Paul Cramer, Björn von Eyss
Yes-associated protein (YAP) and its homolog, transcriptional coactivator with PDZ-binding motif (TAZ), are the main transcriptional downstream effectors of the Hippo pathway. Decreased Hippo pathway activity leads to nuclear translocation of YAP/TAZ where they interact with TEAD transcription factors to induce target gene expression. Unrestrained YAP/TAZ activity can lead to excessive growth and tumor formation in a short time, underscoring the evolutionary need for tight control of these two transcriptional coactivators. Here, we report that the AP-1 component JUN acts as specific repressor of YAP/TAZ at joint target sites to decrease YAP/TAZ activity. This function of JUN is independent of its heterodimeric AP-1 partner FOS and the canonical AP-1 function. Since expression of JUN is itself induced by YAP/TAZ, our work identifies a JUN-dependent negative feedback loop that buffers YAP/TAZ activity at joint genomic sites. This negative feedback loop gets disrupted in liver cancer to unlock the full oncogenic potential of YAP/TAZ. Our results thus demonstrate an additional layer of control for the interplay of YAP/TAZ and AP-1.
{"title":"A non-canonical repressor function of JUN restrains YAP activity and liver cancer growth.","authors":"Yuliya Kurlishchuk, Anita Cindric Vranesic, Marco Jessen, Alexandra Kipping, Christin Ritter, KyungMok Kim, Paul Cramer, Björn von Eyss","doi":"10.1038/s44318-024-00188-0","DOIUrl":"10.1038/s44318-024-00188-0","url":null,"abstract":"<p><p>Yes-associated protein (YAP) and its homolog, transcriptional coactivator with PDZ-binding motif (TAZ), are the main transcriptional downstream effectors of the Hippo pathway. Decreased Hippo pathway activity leads to nuclear translocation of YAP/TAZ where they interact with TEAD transcription factors to induce target gene expression. Unrestrained YAP/TAZ activity can lead to excessive growth and tumor formation in a short time, underscoring the evolutionary need for tight control of these two transcriptional coactivators. Here, we report that the AP-1 component JUN acts as specific repressor of YAP/TAZ at joint target sites to decrease YAP/TAZ activity. This function of JUN is independent of its heterodimeric AP-1 partner FOS and the canonical AP-1 function. Since expression of JUN is itself induced by YAP/TAZ, our work identifies a JUN-dependent negative feedback loop that buffers YAP/TAZ activity at joint genomic sites. This negative feedback loop gets disrupted in liver cancer to unlock the full oncogenic potential of YAP/TAZ. Our results thus demonstrate an additional layer of control for the interplay of YAP/TAZ and AP-1.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11480203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142114395","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 : 2024-10-01Epub Date: 2024-09-04DOI: 10.1038/s44318-024-00207-0
Paulina Kettel, Laura Marosits, Elena Spinetti, Michael Rechberger, Caterina Giannini, Philipp Radler, Isabell Niedermoser, Irmgard Fischer, Gijs A Versteeg, Martin Loose, Roberto Covino, G Elif Karagöz
Conserved signaling cascades monitor protein-folding homeostasis to ensure proper cellular function. One of the evolutionary conserved key players is IRE1, which maintains endoplasmic reticulum (ER) homeostasis through the unfolded protein response (UPR). Upon accumulation of misfolded proteins in the ER, IRE1 forms clusters on the ER membrane to initiate UPR signaling. What regulates IRE1 cluster formation is not fully understood. Here, we show that the ER lumenal domain (LD) of human IRE1α forms biomolecular condensates in vitro. IRE1α LD condensates were stabilized both by binding to unfolded polypeptides as well as by tethering to model membranes, suggesting their role in assembling IRE1α into signaling-competent stable clusters. Molecular dynamics simulations indicated that weak multivalent interactions drive IRE1α LD clustering. Mutagenesis experiments identified disordered regions in IRE1α LD to control its clustering in vitro and in cells. Importantly, dysregulated clustering of IRE1α mutants led to defects in IRE1α signaling. Our results revealed that disordered regions in IRE1α LD control its clustering and suggest their role as a common strategy in regulating protein assembly on membranes.
保守的信号级联可监控蛋白质折叠的平衡,以确保细胞的正常功能。IRE1是进化保守的关键参与者之一,它通过未折叠蛋白反应(UPR)维持内质网(ER)的平衡。当折叠错误的蛋白质在 ER 中积累时,IRE1 会在 ER 膜上形成簇,启动 UPR 信号。目前还不完全清楚是什么在调控 IRE1 簇的形成。在这里,我们发现人类 IRE1α 的 ER 腔域(LD)在体外形成了生物分子凝聚体。IRE1α LD凝聚物通过与未折叠的多肽结合以及与模型膜的系链而稳定,这表明它们在将IRE1α组装成具有信号传导能力的稳定团簇中发挥作用。分子动力学模拟表明,微弱的多价相互作用推动了 IRE1α LD 聚类。突变实验确定了IRE1α LD中的无序区域,以控制其在体外和细胞中的聚类。重要的是,IRE1α突变体的聚类失调导致了IRE1α信号传导的缺陷。我们的研究结果表明,IRE1α LD中的无序区域控制着它的聚类,并表明它们是调节蛋白质在膜上组装的一种常见策略。
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