Geranylgeranylated-SCFFBXO10 Regulates Selective Outer Mitochondrial Membrane Proteostasis and Function.
Geranylgeranylated-SCFFBXO10 Regulates Selective Outer Mitochondrial Membrane Proteostasis and Function.
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Geranylgeranylated-SCFFBXO10 选择性调节线粒体外膜蛋白质稳态和功能。
DOI：
10.1101/2024.04.16.589745
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Kuchay,ShaFi
中科院分区：
文献类型：
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作者：
Bhat,SameerAhmed;Vasi,Zahra;Jiang,Liping;Selvaraj,Shruthi;Ferguson,Rachel;Gudur,Anish;Ismail,Hagar;Adhikari,Ritika;Dhabaria,Avantika;Ueberheide,Beatrix;Kuchay,ShaFi
室特异性细胞膜蛋白的周转尚未得到很好的理解。我们发现，culin - ring -连接酶1复合体的可互换组分FBXO10在半胱氨酸953处被香叶基-香叶基类异戊二烯脂质修饰，促进其动态运输到线粒体外膜（OMM）。FBXO10多肽缺乏标准线粒体靶向序列（MTS）；相反，它在C953上的香叶酰化和与两种细胞质因子的相互作用，即6型磷酸二酯酶的细胞质因子样δ亚基（PDE6δ，一种戊烯基结合蛋白）和热休克蛋白90 （HSP90，一种伴侣蛋白），协调了特异性靶向戊烯基fbxo10的OMM。FBXO10（C953S）突变体从OMM重新分布，损害线粒体ATP的产生和膜电位，并增加断裂。磷酸甘油酸酶-5 （PGAM5）通过富集线粒体的比较定量蛋白质组学鉴定为FBXO10在OMM的潜在底物。FBXO10缺失或表达前置酰化缺陷FBXO10（C953S）抑制PGAM5降解，破坏线粒体稳态，损害人诱导多能干细胞（iPSCs）和小鼠成肌细胞的成肌分化。我们的研究确定了fbxo10介导的选择性线粒体蛋白质停滞调节的机制，可能适合治疗干预。
Compartment-specific cellular membrane protein turnover is not well understood. We show that FBXO10, the interchangeable component of the cullin-RING-ligase 1 complex, undergoes lipid modification with geranylgeranyl isoprenoid at cysteine953, facilitating its dynamic trafficking to the outer mitochondrial membrane (OMM). FBXO10 polypeptide lacks a canonical mitochondrial targeting sequence (MTS); instead, its geranylgeranylation at C953 and interaction with two cytosolic factors, cytosolic factor-like δ subunit of type 6 phosphodiesterase (PDE6δ; a prenyl-group-binding protein) and heat shock protein 90 (HSP90; a chaperone), orchestrate specific OMM targeting of prenyl-FBXO10. The FBXO10(C953S) mutant redistributes away from the OMM, impairs mitochondrial ATP production and membrane potential, and increases fragmentation. Phosphoglycerate mutase-5 (PGAM5) was identified as a potential substrate of FBXO10 at the OMM using comparative quantitative proteomics of enriched mitochondria. FBXO10 loss or expression of prenylation-deficient FBXO10(C953S) inhibited PGAM5 degradation, disrupted mitochondrial homeostasis, and impaired myogenic differentiation of human induced pluripotent stem cells (iPSCs) and murine myoblasts. Our studies identify a mechanism for FBXO10-mediated regulation of selective mitochondrial proteostasis potentially amenable to therapeutic intervention.