Laboratory of Biology of Cytoskeleton, Institute of Molecular Genetics of the Czech Academy of Sciences, CZ 142 20 Prague, Czech Republic.
Section of Neurology, St. Christopher's Hospital for Children, Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA 19134, USA.
Cells. 2022 Feb 5;11(3):555. doi: 10.3390/cells11030555.
ER distribution depends on microtubules, and ER homeostasis disturbance activates the unfolded protein response resulting in ER remodeling. CDK5RAP3 (C53) implicated in various signaling pathways interacts with UFM1-protein ligase 1 (UFL1), which mediates the ufmylation of proteins in response to ER stress. Here we find that UFL1 and C53 associate with γ-tubulin ring complex proteins. Knockout of or in human osteosarcoma cells induces ER stress and boosts centrosomal microtubule nucleation accompanied by γ-tubulin accumulation, microtubule formation, and ER expansion. C53, which is stabilized by UFL1, associates with the centrosome and rescues microtubule nucleation in cells lacking UFL1. Pharmacological induction of ER stress by tunicamycin also leads to increased microtubule nucleation and ER expansion. Furthermore, tunicamycin suppresses the association of C53 with the centrosome. These findings point to a novel mechanism for the relief of ER stress by stimulation of centrosomal microtubule nucleation.
内质网（ER）的分布依赖于微管，内质网的动态平衡受到干扰会激活未折叠蛋白反应，导致内质网重塑。参与多种信号通路的 CDK5RAP3（C53）与 UFM1-蛋白连接酶 1（UFL1）相互作用，UFL1 介导 ER 应激时蛋白质的泛素化。本研究发现 UFL1 和 C53 与 γ-微管蛋白环复合物蛋白（γ-TuRC）相关。在人骨肉瘤细胞中敲除 或 会诱导 ER 应激，增强中心体微管核形成，同时伴随着 γ-微管蛋白积累、微管形成和 ER 扩张。C53 由 UFL1 稳定，与中心体结合，并在缺乏 UFL1 的细胞中拯救微管核形成。用衣霉素诱导 ER 应激也会导致微管核形成增加和 ER 扩张。此外，衣霉素抑制 C53 与中心体的结合。这些发现为通过刺激中心体微管核形成缓解 ER 应激提供了一个新的机制。
