Palmitoylation and PDE6δ regulate membrane-compartment-specific substrate ubiquitylation and degradation.
Palmitoylation and PDE6δ regulate membrane-compartment-specific substrate ubiquitylation and degradation.
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DOI：
10.1016/j.celrep.2023.111999
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发表时间：
2023-01-31
期刊：
影响因子：
8.8
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中科院分区：
文献类型：
--
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底物降解的泛素蛋白酶体系统（UPS）在特定的膜隔室仍然难以捉摸。在这里，我们表明两种脂质修饰和PDE 6 δ的相互作用通过SCFFBXL 2调节隔室底物靶向。FBXL 2在与CaaX基序并列的半胱氨酸417和419上以异戊烯基化依赖性方式被棕榈酰化。棕榈酰化/脱棕榈酰化调节其亚细胞运输以进行底物接合和降解。为了控制其亚细胞分布，脂质修饰的FBXL 2与PDE 6 δ相互作用。扰乱FBXL 2和PDE 6 δ之间的平衡会破坏FBXL 2向所有膜隔室的递送，而脱棕榈酰化的FBXL 2则富集在内质网（ER）上。去棕榈酰化FBXL 2（C417 S/C419 S）促进ER处IP 3R 3的降解，抑制IP 3R 3依赖性线粒体钙超载，并抵消氧化应激时钙依赖性细胞死亡。相反，破坏PDE 6 δ-FBXL 2平衡具有相反的效果。这些发现描述了空间受限底物降解的潜在机制，并表明抑制FBXL 2棕榈酰化和/或与PDE 6 δ结合可能提供治疗益处。Liang等人表明FBXL 2-CRL在C417和C419处被棕榈酰化，与CaaX-异戊二烯化基序并列。脂质修饰的FBXL 2与PDE 6 δ复合调节亚细胞分布。扰乱FBXL 2-PDE 6 δ平衡会破坏FBXL 2向所有膜隔室的递送，而脱棕榈酰化FBXL 2（C417 S/C419 S）在ER富集。描述了通过FBXL 2的空间受限的基板接合/降解机制。
Substrate degradation by the ubiquitin proteasome system (UPS) in specific membrane compartments remains elusive. Here, we show that the interplay of two lipid modifications and PDE6δ regulates compartmental substrate targeting via the SCFFBXL2. FBXL2 is palmitoylated in a prenylation-dependent manner on cysteines 417 and 419 juxtaposed to the CaaX motif. Palmitoylation/depalmitoylation regulates its subcellular trafficking for substrate engagement and degradation. To control its subcellular distribution, lipid-modified FBXL2 interacts with PDE6δ. Perturbing the equilibrium between FBXL2 and PDE6δ disrupts the delivery of FBXL2 to all membrane compartments, whereas depalmitoylated FBXL2 is enriched on the endoplasmic reticulum (ER). Depalmitoylated FBXL2(C417S/C419S) promotes the degradation of IP3R3 at the ER, inhibits IP3R3-dependent mitochondrial calcium overload, and counteracts calcium-dependent cell death upon oxidative stress. In contrast, disrupting the PDE6δ-FBXL2 equilibrium has the opposite effect. These findings describe a mechanism underlying spatially-restricted substrate degradation and suggest that inhibition of FBXL2 palmitoylation and/or binding to PDE6δ may offer therapeutic benefits. Liang et al. show that FBXL2-CRL is palmitoylated at C417 and C419 juxtaposed to CaaX-prenylation-motif. Lipid-modified-FBXL2 in complex with PDE6δ regulates subcellular distribution. Perturbing FBXL2-PDE6δ equilibrium disrupts delivery of FBXL2 to all membrane compartments, whereas depalmitoylated FBXL2(C417S/C419S) is enriched at the ER. Spatially-restricted substrate engagement/degradation mechanism via FBXL2 is described.
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影响因子：
64.8
作者：
Kuchay S;Giorgi C;Simoneschi D;Pagan J;Missiroli S;Saraf A;Florens L;Washburn MP;Collazo-Lorduy A;Castillo-Martin M;Cordon-Cardo C;Sebti SM;Pinton P;Pagano M
通讯作者：
Pagano M
影响因子：
14.8
作者：
Ismail, Shehab A.;Chen, Yong-Xiang;Wittinghofer, Alfred
通讯作者：
Wittinghofer, Alfred
影响因子：
4.1
作者：
Oberdorf, J;Webster, JM;Wojcikiewicz, RJH
通讯作者：
Wojcikiewicz, RJH
影响因子：
5.3
作者：
Chen, Bill B.;Coon, Tiffany A.;Mallampalli, Rama K.
通讯作者：
Mallampalli, Rama K.
影响因子：
16.8
作者：
Kuchay, Shafi;Wang, Hui;Pagano, Michele
通讯作者：
Pagano, Michele