FKBP8 LIRL‐dependent mitochondrial fragmentation facilitates mitophagy under stress conditions
FKBP8 LIRL‐dependent mitochondrial fragmentation facilitates mitophagy under stress conditions
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DOI：
10.1096/fj.201901735r
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发表时间：
2019-12
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影响因子：
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通讯作者：
Seung-Min Yoo;S. Yamashita;Hyunjoo Kim;Do-Hyeong Na;Haneul Lee;Seo Jin Kim;D. Cho;T. Kanki
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文献类型：
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作者：
Seung-Min Yoo;S. Yamashita;Hyunjoo Kim;Do-Hyeong Na;Haneul Lee;Seo Jin Kim;D. Cho;T. Kanki
线粒体质量控制通过调节线粒体动力学和有丝分裂来维持线粒体的功能。尽管线粒体质量控制因素已被确定，但对协调线粒体分裂和有丝分裂的关键调控因子知之甚少。通过基于细胞的功能筛选，FK506结合蛋白8(FKBP8)被鉴定为靶向线粒体微管相关蛋白1轻链3(LC3)并改变线粒体形态的基因。显微镜观察发现，FKBP8基因敲除小鼠胚胎的HeLa细胞和Fkbp8杂合子敲除小鼠胚胎的大脑皮质均可见线粒体管的形成和增大。在缺铁胁迫下，FKBP8通过萌发被募集到线粒体分裂的部位，并与LC3共定位。FKBP8也是低氧应激下线粒体碎裂和有丝分裂所必需的。相反，FKBP8过表达诱导HeLa细胞、人成纤维细胞和小鼠胚胎成纤维细胞(MEF)线粒体断裂，这种断裂在Drp1基因敲除的MEF细胞、FIP200基因敲除的HeLa细胞和BNIP3/Nix双基因敲除的HeLa细胞中发生，而在OPA1基因敲除的MEF中不发生。有趣的是，我们在FKBP8的N端发现了一个LIR基序(LIRL)和一个LIR基序，LIRL对于诱导线粒体断裂和FKBP8与OPA1的结合都是必不可少的。综上所述，我们认为FKBP8在线粒体吞噬过程中通过LIRL起着重要的作用，在胁迫条件下，FKBP8和LIR的这种活性是有丝分裂所必需的。
Mitochondrial quality control maintains mitochondrial function by regulating mitochondrial dynamics and mitophagy. Despite the identification of mitochondrial quality control factors, little is known about the crucial regulators coordinating both mitochondrial fission and mitophagy. Through a cell‐based functional screening assay, FK506 binding protein 8 (FKBP8) was identified to target microtubule‐associated protein 1 light chain 3 (LC3) to the mitochondria and to change mitochondrial morphology. Microscopy analysis revealed that the formation of tubular and enlarged mitochondria was observed in FKBP8 knockdown HeLa cells and the cortex of Fkbp8 heterozygote‐knockout mouse embryos. Under iron depletion‐induced stress, FKBP8 was recruited to the site of mitochondrial division through budding and colocalized with LC3. FKBP8 was also found to be required for mitochondrial fragmentation and mitophagy under hypoxic stress. Conversely, FKBP8 overexpression induced mitochondrial fragmentation in HeLa cells, human fibroblasts and mouse embryo fibroblasts (MEFs), and this fragmentation occurred in Drp1 knockout MEF cells, FIP200 knockout HeLa cells and BNIP3/NIX double knockout HeLa cells, but not in Opa1 knockout MEFs. Interestingly, we found an LIR motif‐like sequence (LIRL), as well as an LIR motif, at the N‐terminus of FKBP8 and LIRL was essential for both inducing mitochondrial fragmentation and binding of FKBP8 to OPA1. Together, we suggest that FKBP8 plays an essential role in mitochondrial fragmentation through LIRL during mitophagy and this activity of FKBP8 together with LIR is required for mitophagy under stress conditions.