FKBP8 recruits LC3A to mediate Parkin-independent mitophagy
FKBP8 recruits LC3A to mediate Parkin-independent mitophagy
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DOI：
10.15252/embr.201643147
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发表时间：
2017-06-01
期刊：
影响因子：
7.7
通讯作者：
Johansen, Terje
中科院分区：
文献类型：
--
作者：
Bhujabal, Zambarlal;Birgisdottir, Asa B.;Johansen, Terje
线粒体自噬（Mitophagy）是细胞自噬过程中的一个重要过程，是通过自噬选择性地清除受损或过量的线粒体。线粒体外膜（OMM）蛋白NIX、BNIP 3、FUNDC 1和Bcl 2-L13在线粒体自噬期间将ATG 8蛋白（LC 3/GABARAP）募集到线粒体。FKBP 8（也称为FKBP 38）是FK 506结合蛋白（FKBP）家族的独特成员，类似地锚定在OMM中，并作为具有抗凋亡活性的多功能衔接子。在酵母双杂交筛选中，我们将FKBP 8鉴定为ATG 8相互作用蛋白。在这里，我们映射的N-末端LC 3相互作用区（LIR）基序FKBP 8强烈结合LC 3A体外和体内。FKBP 8以LIR依赖性方式有效地将脂化的LC 3A募集到受损的线粒体。相反，线粒体自噬受体BNIP 3和NIX即使在线粒体损伤后也不能介导LC 3A的有效募集。FKBP 8与LC 3A的共表达深刻地诱导了不依赖于Parkin的线粒体自噬。引人注目的是，即使作为线粒体自噬受体，FKBP 8也通过逃离线粒体而避免降解。总之，这项研究确定了FKBP 8和LC 3A的新作用，它们共同作用诱导线粒体自噬。
Mitophagy, the selective removal of damaged or excess mitochondria by autophagy, is an important process in cellular homeostasis. The outer mitochondrial membrane (OMM) proteins NIX, BNIP3, FUNDC1, and Bcl2-L13 recruit ATG8 proteins (LC3/GABARAP) to mitochondria during mitophagy. FKBP8 (also known as FKBP38), a unique member of the FK506-binding protein (FKBP) family, is similarly anchored in the OMM and acts as a multifunctional adaptor with anti-apoptotic activity. In a yeast two-hybrid screen, we identified FKBP8 as an ATG8-interacting protein. Here, we map an N-terminal LC3-interacting region (LIR) motif in FKBP8 that binds strongly to LC3A both invitro and in vivo. FKBP8 efficiently recruits lipidated LC3A to damaged mitochondria in a LIR-dependent manner. The mitophagy receptors BNIP3 and NIX in contrast are unable to mediate an efficient recruitment of LC3A even after mitochondrial damage. Co-expression of FKBP8 with LC3A profoundly induces Parkin-independent mitophagy. Strikingly, even when acting as a mitophagy receptor, FKBP8 avoids degradation by escaping from mitochondria. In summary, this study identifies novel roles for FKBP8 and LC3A, which act together to induce mitophagy.