AbstractThe ER-resident proteins VMP1 and TMEM41B share a conserved DedA domain, which confers lipid scramblase activity. Loss of either gene results in embryonic lethality in mice and defects in autophagy and lipid droplet metabolism. To investigate their role in pluripotency and lineage specification, we generated Vmp1 and Tmem41b mutations in mouse embryonic stem cells (ESCs).

摘要ER驻留蛋白VMP1和TMEM41B共享一个保守的DedA结构域，该结构域赋予脂质scramblase活性。任一基因的缺失都会导致小鼠胚胎致死率以及自噬和脂滴代谢缺陷。为了研究它们在多能性和谱系规范中的作用，我们在小鼠胚胎干细胞（ESC）中产生了Vmp1和Tmem41b突变。

We observed that ESCs carrying mutations in Vmp1 and Tmem41b show robust self-renewal and an unperturbed pluripotent expression profile but accumulate LC3-positive autophagosomes and lipid droplets consistent with defects in autophagy and lipid metabolism. ESCs carrying combined mutations in Vmp1 and Tmem41b can differentiate into a wide range of embryonic cell types.

。携带Vmp1和Tmem41b联合突变的胚胎干细胞可以分化为多种胚胎细胞类型。

However, differentiation into primitive endoderm-like cells in culture is impaired, and the establishment of extra-embryonic endoderm stem (XEN) cells is delayed. Mechanistically, we show the deregulation of genes that are associated with WNT signaling. This is further confirmed by cell surface proteome profiling, which identified a significant reduction of the WNT-receptor FZD2 at the plasma membrane in Vmp1 and Tmem41b double mutant ESCs.

然而，在培养物中分化为原始内胚层样细胞受到损害，并且胚胎外内胚层干（XEN）细胞的建立被延迟。从机制上讲，我们显示了与WNT信号相关的基因的失调。细胞表面蛋白质组分析进一步证实了这一点，该分析确定了Vmp1和Tmem41b双突变ESC中质膜上WNT受体FZD2的显着减少。

Importantly, we show that transgenic expression of Fzd2 rescues XEN differentiation. Our findings identify the role of the lipid scramblases VMP1 and TMEM41B in WNT signaling during extra-embryonic endoderm development and characterize their distinct and overlapping functions..

重要的是，我们表明Fzd2的转基因表达可以挽救XEN分化。我们的发现确定了脂质scramblases VMP1和TMEM41B在胚外内胚层发育过程中WNT信号传导中的作用，并表征了它们独特且重叠的功能。。

IntroductionVesicle trafficking and membrane synthesis are intricately interconnected within cellular signaling networks. Lipid scramblases, with their property to shape lipid membrane composition, play a crucial role in facilitating inter-organelle communication. Beyond their integral involvement in maintaining cell homeostasis, recent studies have unveiled their implications in various pathological conditions, such as viral infection [1,2,3,4,5], cancer development [6,7,8,9,10,11], and inflammatory diseases [12,13,14,15,16].

引言囊泡运输和膜合成在细胞信号网络中错综复杂地相互关联。脂质scramblases具有形成脂质膜组成的特性，在促进细胞器间通讯方面起着至关重要的作用。除了参与维持细胞稳态外，最近的研究揭示了它们在各种病理条件下的意义，如病毒感染[1,2,3,4,5]，癌症发展[6,7,8,9,10,11]和炎症性疾病[12,13,14,15,16]。

The vacuole membrane protein 1 (VMP1) and transmembrane protein 41B (TMEM41B) are lipid scramblases with a highly conserved DedA domain [17, 18]. They localize at the ER membrane and are distinguished from other ER-associated flippases or scramblases as they facilitate bi-directional lipid diffusion in an ATP- and Ca2+-independent manner.

液泡膜蛋白1（VMP1）和跨膜蛋白41B（TMEM41B）是具有高度保守的DedA结构域的脂质scramblases[17，18]。它们位于ER膜上，与其他ER相关的翻转酶或scramblases不同，因为它们以不依赖ATP和Ca2+的方式促进双向脂质扩散。

VMP1 and TMEM41B are necessary for autophagosome formation [19, 20], lipid droplet metabolism [17, 21], and lipoprotein formation [22]. Additional reports proposed a more global role in ER protein homeostasis [23] and vesicle transport [24]. Despite multifaceted functions, their absence does not influence cell survival significantly.

VMP1和TMEM41B是自噬体形成[19，20]，脂滴代谢[17，21]和脂蛋白形成[22]所必需的。其他报道提出了ER蛋白稳态（23）和囊泡运输（24）中更具全球性的作用。尽管具有多方面的功能，但它们的缺失不会显着影响细胞存活。

Compensatory mechanisms shared by VMP1 and TMEM41B or other ER scramblases likely maintain cellular homeostasis. While VMP1 depletion leads to a pronounced defect in autophagosome assembly [19, 20], TMEM41B appears to play a pivotal role in sustaining lipid droplet homeostasis and serves as a crucial factor in RNA virus replication [3, 25].

VMP1和TMEM41B或其他ER scramblases共享的补偿机制可能维持细胞稳态。虽然VMP1耗竭导致自噬体组装的明显缺陷[19，20]，但TMEM41B似乎在维持脂滴稳态中起关键作用，并且是RNA病毒复制的关键因素[3，25]。

Differences in cellular systems and depletion methods across studies complicate comparisons of VMP1 and TMEM41B functions. While their role in autophagy has been directly compared [26], similar studies are needed to assess their specificity or red.

不同研究中细胞系统和耗竭方法的差异使VMP1和TMEM41B功能的比较变得复杂。。

Data availability

数据可用性

The transcriptomic data have been deposited on NCBI SRA database under the accession: PRJNA1031567. The proteomic dataset, including raw data, generated tables, and scripts used for the data analysis, is available in the PRIDE repository: PXD053039.

转录组数据已保存在NCBI SRA数据库中，登录号为：PRJNA1031567。PRIDE存储库中提供了蛋白质组数据集，包括原始数据，生成的表和用于数据分析的脚本：PXD053039。

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Download referencesAcknowledgementsWe acknowledge the Functional Genomics Center Zurich (FGCZ) for technical support and Sungsik Lee from ScopeM facility for help on the RF microscopy. We thank G.J. Pereira, C. Fimiani, and U. Sutter for their help with reagents. We thank C. Ciaudo, A.

下载参考文献致谢我们感谢苏黎世功能基因组学中心（FGCZ）的技术支持，以及ScopeM facility的Sungsik Lee在射频显微镜方面的帮助。我们感谢G.J.Pereira，C.Fimiani和U.Sutter在试剂方面的帮助。我们感谢C.Ciaudo，A。

Grison, R. Di Minin, J. Corn, and K. Basler for their helpful discussions. GDM was supported by the ETH Zurich Postdoctoral Fellowship Program as well as the Marie Curie Actions for People COFUND Program.FundingOpen access funding provided by Swiss Federal Institute of Technology Zurich.Author informationAuthor notesFederico UlianaPresent address: Johannes Gutenberg University of Mainz, Mainz, GermanyAuthors and AffiliationsInstitute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, SwitzerlandMarkus Holzner, Tea Sonicki, Hugo Hunn, Weijun Jiang, Anton Wutz & Giulio Di MininInstitute of Biochemistry, Department of Biology, ETH Zurich, Zurich, SwitzerlandFederico Uliana, Vamshidhar R.

Grison，R。Di Minin，J。Corn和K。Basler的有益讨论。GDM得到了苏黎世理工学院博士后奖学金计划以及玛丽·居里人民行动联合基金计划的支持。资金开放获取资金由瑞士苏黎世联邦理工学院提供。。

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PubMed Google ScholarContributionsConceptualization: MH, AW, and GDM; Data curation: MH, FU, VG, and GDM; Formal analysis: MH, TS, HH, FU, VG, and GDM; Funding acquisition: KW, AW, and GDM; Investigation: MH, AW, and GDM; Methodology: MH, TS, HH, FU, VG, WJ, and GDM; Project administration: AW and GDM; Resources: MH, KW, AW, and GDM; Supervision: KW, AW, and GDM; Validation: MH and GDM; Visualization: MH, FU, VG, and GDM; Writing – original draft: MH, AW, and GDM; Writing – review & editing: MH, TS, HH, FU, VG, WJ, KW, AW, and GDM.Corresponding authorsCorrespondence to.

PubMed谷歌学术贡献概念：MH，AW和GDM；数据管理：MH，FU，VG和GDM；；资金收购：KW，AW和GDM；调查：MH，AW和GDM；方法：MH，TS，HH，FU，VG，WJ和GDM；项目管理：AW和GDM；资源：MH，KW，AW和GDM；监督：KW，AW和GDM；验证：MH和GDM；可视化：MH，FU，VG和GDM；写作-原稿：MH，AW和GDM；写作-评论和编辑：MH，TS，HH，FU，VG，WJ，KW，AW和GDM。通讯作者通讯。

Anton Wutz or Giulio Di Minin.Ethics declarations

安东·伍兹或朱利奥·迪米宁。道德宣言

Competing interests

相互竞争的利益

The authors declare no competing interests.

作者声明没有利益冲突。

Ethical approval and consent to participate

道德认可和参与同意

All methods in this study were carried out in strict accordance with relevant ethical guidelines and institutional regulations. The embryonic stem cells (ESCs) used for genome editing were obtained from previously derived sources. No animal models or human patient samples were involved in this research..

本研究中的所有方法均严格按照相关道德准则和机构法规进行。用于基因组编辑的胚胎干细胞（ESC）是从以前的来源获得的。本研究未涉及动物模型或人类患者样本。。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Supplementary informationSupplemental InformationTable_S1-Gene_classesTable_S2-ESC_DSEq2-analysisTable_S3-XEN_DSEq2-analysis_DoubleKOvsWTTable_S4-MS_plasma_membraneVideo S1 - Cardiomyocyte specification in WT EBsVideo S2 - Cardiomyocyte specification in DoubleKO EBsRights and permissions.

Additional informationPublisher的注释Springer Nature在已发布的地图和机构隶属关系中的管辖权主张方面保持中立。补充信息补充信息Table\u S1-Gene\u classesTable\u S2-ESC\u DSEq2-analysisTable\u S3-XEN\u DSEq2-Analysisable\u DoubleKOvsWTTable\u S4-MS\u plasma\u membraneVideo S1-WT EBsVideo S2中的心肌细胞规格-DoubleKO eBS中的心肌细胞规格和权限。

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Reprints and permissionsAbout this articleCite this articleHolzner, M., Sonicki, T., Hunn, H. et al. The scramblases VMP1 and TMEM41B are required for primitive endoderm specification by targeting WNT signaling.

转载和许可本文引用本文Holzner，M.，Sonicki，T.，Hunn，H。等人。通过靶向WNT信号传导，scramblases VMP1和TMEM41B是原始内胚层规范所必需的。

Cell Death Differ (2024). https://doi.org/10.1038/s41418-024-01435-xDownload citationReceived: 13 July 2024Revised: 27 November 2024Accepted: 10 December 2024Published: 18 December 2024DOI: https://doi.org/10.1038/s41418-024-01435-xShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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