Regulating peroxisome–ER contacts via the ACBD5-VAPB tether by FFAT motif phosphorylation and GSK3β

Suzan Kors, Christian Hacker, C. Bolton, R. Maier, L. Reimann, Emily J.A. Kitchener, B. Warscheid, Joseph L. Costello, M. Schrader
{"title":"Regulating peroxisome–ER contacts via the ACBD5-VAPB tether by FFAT motif phosphorylation and GSK3β","authors":"Suzan Kors, Christian Hacker, C. Bolton, R. Maier, L. Reimann, Emily J.A. Kitchener, B. Warscheid, Joseph L. Costello, M. Schrader","doi":"10.1101/2021.11.11.467785","DOIUrl":null,"url":null,"abstract":"Peroxisomes and the endoplasmic reticulum (ER) cooperate in cellular lipid metabolism. They form membrane contacts through interaction of the peroxisomal membrane protein ACBD5 [acyl-coenzyme A-binding domain protein 5] and the ER-resident protein VAPB [vesicle-associated membrane protein-associated protein B]. ACBD5 binds to the major sperm protein domain of VAPB via its FFAT-like [two phenylalanines (FF) in an acidic tract] motif. However, molecular mechanisms, which regulate formation of these membrane contact sites, are unknown. Here, we reveal that peroxisome-ER associations via the ACBD5-VAPB tether are regulated by phosphorylation. We show that ACBD5-VAPB binding is phosphatase-sensitive and identify phosphorylation sites in the flanking regions and core of the FFAT-like motif, which alter interaction with VAPB and thus, peroxisome-ER contact sites differently. Moreover, we demonstrate that GSK3β [glycogen synthase kinase-3 beta] regulates this interaction. Our findings reveal for the first time a molecular mechanism for the regulation of peroxisome-ER contacts in mammalian cells and expand the current model of FFAT motifs and VAP interaction. SUMMARY Kors et al. reveal that peroxisome-ER associations via the ACBD5-VAPB tether are regulated by phosphorylation and GSK3β in mammalian cells. Phosphorylation sites in the FFAT-like motif of ACBD5 affect the binding to VAPB and thus, peroxisome-ER contact sites, differently.","PeriodicalId":343306,"journal":{"name":"The Journal of Cell Biology","volume":"632 1","pages":"0"},"PeriodicalIF":0.0000,"publicationDate":"2021-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"17","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Journal of Cell Biology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/2021.11.11.467785","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 17

Abstract

Peroxisomes and the endoplasmic reticulum (ER) cooperate in cellular lipid metabolism. They form membrane contacts through interaction of the peroxisomal membrane protein ACBD5 [acyl-coenzyme A-binding domain protein 5] and the ER-resident protein VAPB [vesicle-associated membrane protein-associated protein B]. ACBD5 binds to the major sperm protein domain of VAPB via its FFAT-like [two phenylalanines (FF) in an acidic tract] motif. However, molecular mechanisms, which regulate formation of these membrane contact sites, are unknown. Here, we reveal that peroxisome-ER associations via the ACBD5-VAPB tether are regulated by phosphorylation. We show that ACBD5-VAPB binding is phosphatase-sensitive and identify phosphorylation sites in the flanking regions and core of the FFAT-like motif, which alter interaction with VAPB and thus, peroxisome-ER contact sites differently. Moreover, we demonstrate that GSK3β [glycogen synthase kinase-3 beta] regulates this interaction. Our findings reveal for the first time a molecular mechanism for the regulation of peroxisome-ER contacts in mammalian cells and expand the current model of FFAT motifs and VAP interaction. SUMMARY Kors et al. reveal that peroxisome-ER associations via the ACBD5-VAPB tether are regulated by phosphorylation and GSK3β in mammalian cells. Phosphorylation sites in the FFAT-like motif of ACBD5 affect the binding to VAPB and thus, peroxisome-ER contact sites, differently.
通过FFAT基序磷酸化和GSK3β通过ACBD5-VAPB系链调节过氧化物酶体-内质网接触
过氧化物酶体和内质网(ER)共同参与细胞脂质代谢。它们通过过氧化物酶体膜蛋白ACBD5[酰基辅酶a结合域蛋白5]和er驻留蛋白VAPB[囊泡相关膜蛋白相关蛋白B]的相互作用形成膜接触。ACBD5通过其FFAT-like[酸性通道中的两个苯丙氨酸(FF)]基序结合到VAPB的主要精子蛋白结构域。然而,调控这些膜接触位点形成的分子机制尚不清楚。在这里,我们揭示了通过ACBD5-VAPB系链的过氧化物酶体- er关联受磷酸化调节。我们发现ACBD5-VAPB结合是磷酸酶敏感的,并且鉴定了ffat样基序的侧翼区域和核心的磷酸化位点,这些磷酸化位点改变了与VAPB的相互作用,从而改变了过氧化物酶体-内质网的接触位点。此外,我们证明GSK3β[糖原合成酶激酶-3 β]调节这种相互作用。我们的研究结果首次揭示了哺乳动物细胞中过氧化物酶体-内质网接触调控的分子机制,并扩展了目前FFAT基序和VAP相互作用的模型。Kors等人发现,在哺乳动物细胞中,过氧化物酶体-内质网通过ACBD5-VAPB系链结合受磷酸化和GSK3β调节。ACBD5的ffat样基序的磷酸化位点不同地影响与VAPB的结合,从而影响过氧化物酶体-内质网的接触位点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
自引率
0.00%
发文量
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信