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A regulatory module mediating temperature control of cell-cell communication facilitates tree bud dormancy release. 介导细胞间通信温度控制的调节模块有助于树芽休眠的解除。
IF 9.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-03 DOI: 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.

通过质膜(PD)控制细胞间的通讯在植物发育过程中起着关键作用。在树芽中,低温条件(LT)会诱导质点从闭合状态转换为开放状态,从而恢复芽顶的细胞间通讯并解除休眠。利用遗传学和细胞生物学方法,我们确定了一种以前未曾描述过的转录因子--低温诱导 MADS-box 1(LIM1)--是一种由低温诱导的赤霉素(GA)途径的直接上游激活因子。LIM1-GA 模块通过负向调节胼胝质的积累来促进休眠的解除,从而介导低温诱导的质膜开放。LIM1 还能激活另一个低温诱导因子 FT1(FLOWERING LOCUS T)的表达,LIM1-FT1 形成了一个连贯的前馈回路,汇聚到休眠释放过程中赤霉素信号的低温调控上。数学建模和实验验证表明,赤霉素对 LIM1 的负反馈调控可能在维持花蕾对低温反应的稳健时间调控中发挥关键作用。这些结果揭示了将细胞-细胞通讯的温度控制与对树木适应至关重要的季节性生长调控联系起来的遗传因素。
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引用次数: 0
A cofactor-induced repressive type of transcription factor condensation can be induced by synthetic peptides to suppress tumorigenesis. 合成肽可诱导一种由辅助因子诱导的抑制型转录因子凝聚,从而抑制肿瘤发生。
IF 9.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-02 DOI: 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.

转录因子(TF)通过对基因表达进行不同程度的调节,成为细胞死亡和存活的关键决定因素。在这里,我们发现了包括 TEAD4 在内的许多 TFs,它们在受压细胞中形成凝聚体。与YAP诱导的TEAD4转录激活凝聚体不同,我们发现VGLL4和RFXANK等辅助因子可交替诱导抑制性TEAD4凝聚体,从而在葡萄糖饥饿时引发细胞死亡。以 VGLL4 为重点,我们证明了 TEAD4 和 VGLL4 之间的异型相互作用有利于具有非典型抑制功能的大型 TEAD4 凝聚体的寡聚和组装,即导致 DNA/染色质聚集和缠结,最终阻碍基因表达。基于这些发现,我们设计了一种源自 VGLL4 的 TEAD4 结合基序的多肽,以选择性地诱导 TEAD4 抑制性凝集。这种 "胶水 "肽通过抑制 TEAD4 相关基因的转录,在胃癌基因模型和异种移植小鼠模型中显示出强大的抗肿瘤作用。这种新型抑制性 TF 相分离体现了辅助因子如何协调特定 TF 的相反功能,并通过人工诱导抑制性凝聚提供了潜在的抗肿瘤新策略。
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引用次数: 0
Reassessing the unifying hypothesis for hypercontractility caused by myosin mutations in hypertrophic cardiomyopathy. 重新评估肥厚型心肌病肌球蛋白突变导致的过度收缩统一假说。
IF 9.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-27 DOI: 10.1038/s44318-024-00199-x
James A Spudich, Neha Nandwani, Julien Robert-Paganin, Anne Houdusse, Kathleen M Ruppel
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引用次数: 0
Mouse models to investigate in situ cell fate decisions induced by p53. 研究 p53 诱导的原位细胞命运决定的小鼠模型。
IF 9.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-19 DOI: 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.

研究转录因子如何控制复杂的细胞过程需要一些工具,这些工具可以在单细胞水平上对反应进行可视化,并随时间推移跟踪其细胞命运。例如,肿瘤抑制因子 p53(在人类中也称为 TP53,在小鼠中则称为 TRP53)可以通过转录激活其靶基因来启动多种细胞反应:Puma诱导细胞凋亡,p21诱导细胞周期停滞/细胞衰老。然而,这些过程在不同类型的细胞中是如何调节和启动的尚不清楚。此外,p53 的相互作用伙伴和结合位点在很大程度上仍然难以捉摸。为了研究这些问题,我们在此开发了表达三重-FLAG 标记 p53 的基因敲入小鼠,以促进 p53 的下拉,并开发了两种 p53 反应报告小鼠,分别在 Puma/Bbc3 和 p21 基因位点敲入 tdTomato 和 GFP。通过将这些报告小鼠与 p53 缺陷背景杂交,我们发现新的报告小鼠能可靠地在体外和体内分别报告依赖 p53 和不依赖 p53 的细胞凋亡或细胞周期停滞/衰老程序的启动情况。
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引用次数: 0
Structure of tetrameric forms of the serotonin-gated 5-HT3A receptor ion channel. 羟色胺门控 5-HT3A 受体离子通道的四聚体结构。
IF 9.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-09-04 DOI: 10.1038/s44318-024-00191-5
Bianca Introini, Wenqiang Cui, Xiaofeng Chu, Yingyi Zhang, Ana Catarina Alves, Luise Eckhardt-Strelau, Sabrina Golusik, Menno Tol, Horst Vogel, Shuguang Yuan, Mikhail Kudryashev

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.

多聚膜蛋白在内质网中产生,并被运输到其目标膜上,对于离子通道来说,目标膜通常是质膜。尽管有许多完全组装的通道结构,但我们对组装中间体、多聚体组装机制以及非标准组装的潜在功能的了解还很有限。我们证明了五聚体配体门控血清素 5-HT3A 受体(5-HT3AR)可以组装成四聚体形式,并利用冷冻电镜和断层扫描技术报告了细胞衍生微囊质膜和膜记忆体中的四聚体结构。四聚体结构具有近乎对称的跨膜结构域和不对称的胞外结构域,并能与血清素分子结合。根据我们的冷冻电镜结构进行的计算机模拟破解了五聚体 5-HT3R 的组装途径,并提出了四聚体受体的潜在功能作用。
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引用次数: 0
The fitness cost of spurious phosphorylation. 虚假磷酸化的健康代价
IF 9.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-09-10 DOI: 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.

信号转导的保真度要求调控分子与其同源靶标结合。然而,拥挤的细胞内部存在着功能上不相关的蛋白质之间发生脱靶相互作用的风险。这种脱靶相互作用如何影响适存性尚不清楚。在这里,我们利用酿酒酵母诱导表达酪氨酸激酶。由于酵母缺乏真正的酪氨酸激酶,因此产生的酪氨酸磷酸化在生物学上是假的。我们设计了 44 株酵母菌株,每株表达一种酪氨酸激酶,并对其磷酸化蛋白组进行了定量分析。分析结果显示,约有 30,000 个磷酸化位点映射到约 3500 个蛋白质上。产生的虚假 pY 位点数量与生长下降密切相关,我们预测超过 1000 个 pY 事件是有害的。不过,我们也发现,许多虚假 pY 位点对适应性的影响可以忽略不计,这可能是因为它们的化学计量较低。这一结果与我们的进化分析表明在具有酪氨酸激酶的物种中缺乏磷酸化酪氨酸反选择的结果是一致的。我们的研究结果表明,随着相互作用网络的进化,除了毒性风险之外,细胞还能容忍很大程度的无功能串扰。
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引用次数: 0
Author Correction: BCL7A-containing SWI/SNF/BAF complexes modulate mitochondrial bioenergetics during neural progenitor differentiation. 作者更正:含 BCL7A 的 SWI/SNF/BAF 复合物在神经祖细胞分化过程中调节线粒体生物能。
IF 9.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-01 DOI: 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}
引用次数: 0
The unfolded protein response regulates ER exit sites via SNRPB-dependent RNA splicing and contributes to bone development. 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。
IF 9.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-19 DOI: 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。
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引用次数: 0
A non-canonical repressor function of JUN restrains YAP activity and liver cancer growth. JUN的非典型抑制功能可抑制YAP的活性和肝癌的生长。
IF 9.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-29 DOI: 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.

是相关蛋白(YAP)及其同源物--具有 PDZ 结合基调的转录辅激活因子(TAZ)是 Hippo 通路的主要转录下游效应因子。Hippo 通路活性的降低会导致 YAP/TAZ 的核转位,它们在核转位中与 TEAD 转录因子相互作用,诱导目标基因的表达。不受约束的 YAP/TAZ 活性可在短时间内导致过度生长和肿瘤形成,这突出表明了对这两种转录辅激活因子进行严格控制的进化需要。在这里,我们报告了 AP-1 成分 JUN 在联合靶位点作为 YAP/TAZ 的特异性抑制因子来降低 YAP/TAZ 的活性。JUN 的这种功能与其异源 AP-1 伙伴 FOS 和典型 AP-1 功能无关。由于 JUN 的表达本身就受到 YAP/TAZ 的诱导,我们的研究发现了一个依赖 JUN 的负反馈环,它可以缓冲 YAP/TAZ 在联合基因组位点的活性。这一负反馈环在肝癌中被破坏,从而释放出 YAP/TAZ 的全部致癌潜能。因此,我们的研究结果表明,YAP/TAZ 和 AP-1 的相互作用又多了一层控制。
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引用次数: 0
Disordered regions in the IRE1α ER lumenal domain mediate its stress-induced clustering. IRE1α ER内腔结构域中的紊乱区域介导了其应激诱导的聚类。
IF 9.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-09-04 DOI: 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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