USP19 promotes hypoxia-induced mitochondrial division via FUNDC1 at ER-mitochondria contact sites.
USP19 promotes hypoxia-induced mitochondrial division via FUNDC1 at ER-mitochondria contact sites.
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USP19 通过 ER-线粒体接触位点的 FUNDC1 促进缺氧诱导的线粒体分裂
DOI：
10.1083/jcb.202010006
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发表时间：
2021-07-05
期刊：
影响因子：
--
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Chai P;Cheng Y;Hou C;Yin L;Zhang D;Hu Y;Chen Q;Zheng P;Teng J;Chen J
内质网-线粒体接触对细胞压力做出反应。Chai等人。研究发现，作为对缺氧的响应，USP19是一种内质网驻留的去泛素酶，它聚集在ER-线粒体接触部位，在那里USP19去泛素化并稳定Fundc1，从而促进Drp1的寡聚化和随后的缺氧诱导的线粒体分裂。内质网与线粒体紧密相连，线粒体蛋白Fundc1将Drp1招募到内质网-线粒体接触部位，从而促进线粒体分裂，防止线粒体经历低氧应激。然而，内质网调控缺氧诱导的线粒体分裂的机制尚不清楚。在这里，我们证明了USP19，一个内质网驻留的脱泛素酶，在低氧下聚集在内质网-线粒体接触部位，并促进低氧诱导的线粒体分裂。作为对低氧的响应，USP19在内质网-线粒体接触部位结合并去泛素化Fundc1，促进Drp1寡聚和Drp1 GTP结合和水解酶活性，从而促进线粒体分裂。我们的发现揭示了一种独特的低氧反应途径，该途径由调节线粒体动力学的ER蛋白介导。
ER-mitochondria contacts respond to cellular stress. Chai et al. reveal that in response to hypoxia, USP19, an ER-resident deubiquitinase, accumulates at ER-mitochondria contact sites where USP19 deubiquitinates and stabilizes FUNDC1, thereby promoting Drp1 oligomerization and subsequent hypoxia-induced mitochondria division. The ER tethers tightly to mitochondria and the mitochondrial protein FUNDC1 recruits Drp1 to ER-mitochondria contact sites, subsequently facilitating mitochondrial fission and preventing mitochondria from undergoing hypoxic stress. However, the mechanisms by which the ER modulates hypoxia-induced mitochondrial fission are poorly understood. Here, we show that USP19, an ER-resident deubiquitinase, accumulates at ER-mitochondria contact sites under hypoxia and promotes hypoxia-induced mitochondrial division. In response to hypoxia, USP19 binds to and deubiquitinates FUNDC1 at ER-mitochondria contact sites, which facilitates Drp1 oligomerization and Drp1 GTP-binding and hydrolysis activities, thereby promoting mitochondrial division. Our findings reveal a unique hypoxia response pathway mediated by an ER protein that regulates mitochondrial dynamics.
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