State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China.
Department of Clinical Immunology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Nat Struct Mol Biol. 2024 Feb;31(2):219-231. doi: 10.1038/s41594-023-01165-7. Epub 2024 Jan 4.
Morphological rearrangement of the endoplasmic reticulum (ER) is critical for metazoan mitosis. Yet, how the ER is remodeled by the mitotic signaling remains unclear. Here, we report that mitotic Aurora kinase A (AURKA) employs a small GTPase, Rab1A, to direct ER remodeling. During mitosis, AURKA phosphorylates Rab1A at Thr75. Structural analysis demonstrates that Thr75 phosphorylation renders Rab1A in a constantly active state by preventing interaction with GDP-dissociation inhibitor (GDI). Activated Rab1A is retained on the ER and induces the oligomerization of ER-shaping protein RTNs and REEPs, eventually triggering an increase of ER complexity. In various models, from Caenorhabditis elegans and Drosophila to mammals, inhibition of Rab1A phosphorylation by genetic modifications disrupts ER remodeling. Thus, our study reveals an evolutionarily conserved mechanism explaining how mitotic kinase controls ER remodeling and uncovers a critical function of Rab GTPases in metaphase.
内质网（ER）的形态重排对于后生动物有丝分裂至关重要。然而，有丝分裂信号如何重塑 ER 仍不清楚。在这里，我们报告说有丝分裂的极光激酶 A（AURKA）利用小 GTPase Rab1A 来指导 ER 重塑。在有丝分裂过程中，AURKA 将 Thr75 磷酸化到 Rab1A 上。结构分析表明，Thr75 磷酸化通过防止与 GDP 解离抑制剂（GDI）相互作用使 Rab1A 处于持续活跃状态。激活的 Rab1A 保留在 ER 上，并诱导 ER 成形蛋白 RTNs 和 REEPs 的寡聚化，最终引发 ER 复杂性的增加。在各种模型中，从秀丽隐杆线虫和果蝇到哺乳动物，通过遗传修饰抑制 Rab1A 磷酸化会破坏 ER 重塑。因此，我们的研究揭示了一种进化上保守的机制，解释了有丝分裂激酶如何控制 ER 重塑，并揭示了 Rab GTPases 在中期的关键功能。
