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Torsin and NEP1R1-CTDNEP1 phosphatase affect interphase nuclear pore complex insertion by lipid-dependent and lipid-independent mechanisms
The EMBO Journal ( IF 11.4 ) Pub Date : 2021-07-27 , DOI: 10.15252/embj.2020106914
Julie Jacquemyn 1, 2 , Joyce Foroozandeh 1, 2 , Katlijn Vints 1, 2, 3 , Jef Swerts 1, 2 , Patrik Verstreken 1, 2 , Natalia V Gounko 1, 2, 3 , Sandra F Gallego 1, 2 , Rose Goodchild 1, 2
Affiliation  

The interphase nuclear envelope (NE) is extensively remodeled during nuclear pore complex (NPC) insertion. How this remodeling occurs and why it requires Torsin ATPases, which also regulate lipid metabolism, remains poorly understood. Here, we show that Drosophila Torsin (dTorsin) affects lipid metabolism via the NEP1R1-CTDNEP1 phosphatase and the Lipin phosphatidic acid (PA) phosphatase. This includes that Torsins remove NEP1R1-CTDNEP1 from the NE in fly and mouse cells, leading to subsequent Lipin exclusion from the nucleus. NEP1R1-CTDNEP1 downregulation also restores nuclear pore membrane fusion in post-mitotic dTorsinKO fat body cells. However, dTorsin-associated nuclear pore defects do not correlate with lipidomic abnormalities and are not resolved by silencing of Lipin. Further testing confirmed that membrane fusion continues in cells with hyperactivated Lipin. It also led to the surprising finding that excessive PA metabolism inhibits recruitment of the inner ring complex Nup35 subunit, resulting in elongated channel-like structures in place of mature nuclear pores. We conclude that the NEP1R1-CTDNEP1 phosphatase affects interphase NPC biogenesis by lipid-dependent and lipid-independent mechanisms, explaining some of the pleiotropic effects of Torsins.

中文翻译:

Torsin 和 NEP1R1-CTDNEP1 磷酸酶通过脂质依赖性和脂质非依赖性机制影响相间核孔复合物插入

在核孔复合物 (NPC) 插入过程中,相间核膜 (NE) 被广泛重塑。这种重塑是如何发生的,以及为什么它需要 Torsin ATPases,它也调节脂质代谢,仍然知之甚少。在这里,我们显示果蝇Torsin (dTorsin) 通过 NEP1R1-CTDNEP1 磷酸酶和脂质磷脂酸 (PA) 磷酸酶影响脂质代谢。这包括 Torsins 从果蝇和小鼠细胞的 NE 中去除 NEP1R1-CTDNEP1,导致随后的 Lipin 从细胞核中排除。NEP1R1-CTDNEP1 下调也恢复了有丝分裂后dTorsin KO 中的核孔膜融合脂肪体细胞。然而,dTorsin 相关的核孔缺陷与脂质组学异常无关,并且不能通过 Lipin 的沉默来解决。进一步的测试证实膜融合在具有过度活化的 Lipin 的细胞中继续进行。它还导致了一个令人惊讶的发现,即过度的 PA 代谢抑制了内环复合体 Nup35 亚基的募集,导致拉长的通道状结构代替成熟的核孔。我们得出结论,NEP1R1-CTDNEP1 磷酸酶通过脂质依赖性和脂质非依赖性机制影响相间 NPC 生物发生,解释了 Torsins 的一些多效作用。
更新日期:2021-09-01
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