功能重叠的溶酶体内和溶酶体外途径促进哺乳动物细胞中双（单酰基甘油）磷酸的合成-动脉网

Functionally overlapping intra- and extralysosomal pathways promote bis(monoacylglycero)phosphate synthesis in mammalian cells

Nature 等信源发布 2024-11-16 11:08

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AbstractBis(monoacylglycero)phosphate (BMP) is a major phospholipid constituent of intralumenal membranes in late endosomes/lysosomes, where it regulates the degradation and sorting of lipid cargo. Recent observations suggest that the Batten disease-associated protein CLN5 functions as lysosomal BMP synthase.

摘要双（单酰基甘油）磷酸盐（BMP）是晚期内体/溶酶体中腔内膜的主要磷脂成分，它调节脂质货物的降解和分选。最近的观察表明，巴滕病相关蛋白CLN5起溶酶体BMP合酶的作用。

Here, we show that transacylation reactions catalyzed by cytosolic and secreted enzymes enhance BMP synthesis independently of CLN5. The transacylases identified in this study are capable of acylating the precursor lipid phosphatidylglycerol (PG), generating acyl-PG, which is subsequently hydrolyzed to BMP.

在这里，我们显示由胞质和分泌酶催化的转酰化反应独立于CLN5增强BMP合成。本研究中鉴定的转酰化酶能够酰化前体脂质磷脂酰甘油（PG），产生酰基PG，随后将其水解为BMP。

Extracellularly, acyl-PG and BMP are generated by endothelial lipase in cooperation with other serum enzymes of the pancreatic lipase family. The intracellular acylation of PG is catalyzed by several members of the cytosolic phospholipase A2 group IV (PLA2G4) family. Overexpression of secreted or cytosolic transacylases was sufficient to correct BMP deficiency in HEK293 cells lacking CLN5.

细胞外，酰基PG和BMP由内皮脂肪酶与胰脂肪酶家族的其他血清酶协同产生。PG的细胞内酰化由胞质磷脂酶A2 IV组（PLA2G4）家族的几个成员催化。分泌型或胞质转酰酶的过表达足以纠正缺乏CLN5的HEK293细胞中BMP的缺乏。

Collectively, our observations suggest that functionally overlapping pathways promote BMP synthesis in mammalian cells..

总的来说，我们的观察结果表明，功能重叠的途径促进了哺乳动物细胞中BMP的合成。。

IntroductionCells take up nutrients, ligands, and components of the plasma membrane via the endocytic pathway. This pathway is essential for maintaining metabolic homeostasis and is composed of organelles that undergo a dynamic transformation, comprising early endosomes, multivesicular bodies, late endosomes (LE), and lysosomes.

引言细胞通过内吞途径吸收营养物质，配体和质膜成分。该途径对于维持代谢稳态至关重要，并且由经历动态转化的细胞器组成，包括早期内体，多囊体，晚期内体（LE）和溶酶体。

During maturation, the inward budding of the limiting endosomal membrane produces intralumenal vesicles (ILVs), which results in the formation of multivesicular organelles. This process is essential for organelle maturation and proper cargo sorting1. ILVs undergo remodeling during organelle maturation leading to substantial changes in lipid composition2.

在成熟过程中，限制性内体膜的向内萌芽产生腔内囊泡（ILV），这导致多囊细胞器的形成。这个过程对于细胞器成熟和正确的货物分类至关重要1。ILV在细胞器成熟过程中发生重塑，导致脂质组成发生实质性变化2。

Bis(monoacylglycero)phosphate (BMP), also known as lysobisphosphatidic acid (LBPA), is a major lipid constituent of internal membranes of LE and lysosomes2. This phospholipid interacts with many lumenal proteins and thereby promotes the degradation and export of lipid cargo3,4.The availability of lumenal membranes in lysosomes is particularly important for lipid hydrolases, since these enzymes require a water-lipid interphase for activation5.

双（单酰基甘油）磷酸盐（BMP），也称为溶血磷脂酸（LBPA），是LE和溶酶体内膜的主要脂质成分2。这种磷脂与许多管腔蛋白相互作用，从而促进脂质货物的降解和输出3,4。溶酶体中管腔膜的可用性对于脂质水解酶特别重要，因为这些酶需要水-脂质界面来激活5。

BMP is negatively charged and highly resistant to degradation in the acidic lysosomal compartments. Based on these features, it can form a docking station for lumenal hydrolases that are positively charged at acidic pH5. Accordingly, it has been shown that BMP stimulates the activity of lysosomal lipid hydrolases catalyzing the degradation of glycerophospholipids, sphingolipids, and neutral lipids5,6.BMP also interacts with lipid-binding and -transport proteins.

BMP带负电荷，对酸性溶酶体区室中的降解具有高度抗性。基于这些特征，它可以为在酸性pH5下带正电荷的内腔水解酶形成对接站。因此，已经表明BMP刺激溶酶体脂质水解酶的活性，催化甘油磷脂，鞘脂和中性脂质的降解5,6.BMP还与脂质结合和转运蛋白相互作用。

It supports the presentation of glycolipids to catabolic enzymes by sphingolipid activator proteins7,8. Furthermore, BMP facilitates cholesterol export from lysosomes9,10, which depends on Niemann-P.

它支持鞘脂激活蛋白7,8将糖脂呈递给分解代谢酶。此外，BMP促进溶酶体9,10的胆固醇输出，这取决于Niemann-P。

Data availability

数据可用性

Source data are provided with this paper as a Source Data file. The validation of the screening library, TLCs, and Western blots generated in this study have been deposited at Mendeley Data (DOI:10.17632/6447jjvd9r.1) and are openly accessible. Source data are provided with this paper.

本文提供了源数据作为源数据文件。本研究中产生的筛选文库，TLC和蛋白质印迹的验证已保存在Mendeley Data（DOI:10.17632/6447JVD9R.1）中，并且可以公开获取。本文提供了源数据。

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Download referencesAcknowledgementsWe want to thank Kathrin A. Zierler, Birgit Juritsch, and Sharon Fiorin for animal care and genotyping. We also thank R. Farese, T. Walther, and Shubham Singh (Sloan Kettering Institute, NY) for helpful discussions. Funding: this work was supported by SFB Lipid hydrolysis (10.55776/F73, D.K., R.Z.), 10.55776/P28533 (R.Z.), 10.55776/P35532 (R.Z.), the doctoral program doc-fund “Molecular Metabolism” 10.55776/DOC50 funded by the Austrian Science Fund FWF, Field of Excellence BioHealth – University of Graz, Graz, Austria, Province of Styria, City of Graz, BioTechMed-Graz, and NAWI Graz, and the Glycolipidologue Program of RIKEN (P.G.).

下载参考文献致谢我们要感谢Kathrin A.Zierler，Birgit Juritsch和Sharon Fiorin的动物护理和基因分型。我们还要感谢R.Farese，T.Walther和Shubham Singh（纽约斯隆凯特琳研究所）的有益讨论。。

For open access purposes, the authors have applied a CC BY public copyright license to any author accepted manuscript version arising from this submission.Author informationAuthor notesThese authors contributed equally: Dominik Bulfon, Johannes Breithofer.Authors and AffiliationsInstitute of Molecular Biosciences, University of Graz, Graz, AustriaDominik Bulfon, Johannes Breithofer, Nermeen Fawzy, Heimo Wolinski, Lennart Hartig, Martin Tischitz, Clara Zitta, Greta Bramerdorfer, Achim Lass, Ulrike Taschler & Robert ZimmermannGottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Graz, AustriaGernot F.

。作者信息作者注意到这些作者做出了同样的贡献：Dominik Bulfon，Johannes Breithofer。作者和附属机构格拉茨大学分子生物科学研究所，格拉茨，澳大利亚布拉丰，约翰内斯·布雷托夫，内梅恩·法兹，海莫·沃林斯基，伦纳德·哈提格，马丁·蒂希茨，克拉拉·齐塔，格雷塔·布拉默多夫，阿希姆·拉斯乌尔里克·塔施勒和罗伯特·齐默尔曼·戈特弗里德·沙茨研究中心，格拉茨医科大学分子生物学和生物化学，澳大利亚格拉茨。

Grabner, Anita Pirchheim, Dagmar Kolb & Dagmar KratkyField of Excellence BioHealth, University of Graz, Graz, AustriaHeimo Wolinski, Achim Lass & Robert ZimmermannCore Facility Ultrastructure Analysis, Center for Medical Research, Medical University of Graz, Graz, AustriaDagmar KolbBioTechMed-Graz, Graz, AustriaDagmar Kratky & Robert ZimmermannLaboratory for Cell Function Dynamics, Center for Brain Science, RIKEN, Wako, Saitama, JapanPeter GreimelAuthor.

Grabner，Anita Pirchheim，Dagmar Kolb＆Dagmar KratkyField of Excellence BioHealth，格拉茨大学，格拉茨，Australiaheimo Wolinski，Achim-Lass＆Robert ZimmermannCore设施超微结构分析，格拉茨医科大学医学研究中心，格拉茨，澳大利亚格拉茨KolbBioTechMed Graz，格拉茨，Australiadagmar Kratky＆Robert Zimmermann细胞功能动力学实验室，大脑科学中心，理研，Wako，Saitama，JapanPeter GreimelAuthor。

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PubMed Google ScholarContributionsConceptualization, D.K., P.G., and R.Z.; Methodology, D.B., J.B., G.G., N.F., M.T., C.Z, A.P., G.B., H.W. and D.Ko.; Validation, L.H., A.L., and U.T., and N.C.; Formal Analysis; D.B., J.B., G.G., N.F., A.P., and D.Ko.; Investigation, D.B., J.B., G.G., N.F., M.T., C.Z, A.P., H.W.

PubMed谷歌学术贡献概念化，D.K.，P.G。和R.Z。；方法论，D.B.，J.B.，G.G.，N.F.，M.T.，C.Z，A.P.，G.B.，H.W.和D.Ko。；验证，L.H.，A.L。和U.T。和N.C。；形式分析；D、 B.，J.B.，G.G.，N.F.，A.P。和D.Ko。；调查，D.B.，J.B.，G.G.，N.F.，M.T.，C.Z，A.P.，H.W。

and D.Ko.; Writing – Original Draft, D.B., D.K., P.G., and R.Z.; Visualization, D.B., J.B., G.G., H.W. and D.Ko.; Supervision, D.K., A.L., and R.Z.Corresponding authorCorrespondence to.

和D.Ko。；写作-原稿，D.B.，D.K.，P.G。和R.Z。；可视化，D.B.，J.B.，G.G.，H.W.和D.Ko。；监督，D.K.，A.L。和R.Z.通讯作者。

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罗伯特·齐默尔曼。道德宣言

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The authors declare no competing interests.

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Reprints and permissionsAbout this articleCite this articleBulfon, D., Breithofer, J., Grabner, G.F. et al. Functionally overlapping intra- and extralysosomal pathways promote bis(monoacylglycero)phosphate synthesis in mammalian cells.

转载和许可本文引用本文Bulfon，D.，Breithofer，J.，Grabner，G.F。等人。功能重叠的溶酶体内和溶酶体外途径促进哺乳动物细胞中双（单酰基甘油）磷酸盐的合成。

Nat Commun 15, 9937 (2024). https://doi.org/10.1038/s41467-024-54213-1Download citationReceived: 27 June 2023Accepted: 03 November 2024Published: 16 November 2024DOI: https://doi.org/10.1038/s41467-024-54213-1Share 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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