Ceglowski J, Hoffman H K, Hoff K J, McCurdy B L, Moore J K, Prekeris R
Department of Cell and Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80015.
bioRxiv. 2023 Jul 25:2023.07.25.550533. doi: 10.1101/2023.07.25.550533.
The primary cilium is a critical sensory organelle that is built of axonemal microtubules ensheathed by a ciliary membrane. In polarized epithelial cells, primary cilia reside on the apical surface and must extend these microtubules directly into the extracellular space and remain a stable structure. However, the factors regulating cross-talk between ciliation and cell polarization, as well as, axonemal microtubule growth and stabilization in polarized epithelia are not fully understood. In this study, we find TTLL12, a previously uncharacterized member of the Tubulin Tyrosine Ligase-Like (TTLL) family, localizes to the base of primary cilia and is required for cilia formation in polarized renal epithelial cells. We also show that TTLL12 directly binds to the α/β-tubulin heterodimer and regulates microtubule dynamics, stability, and post-translational modifications (PTMs). While all other TTLLs catalyze the addition of glutamate or glycine to microtubule C-terminal tails, TTLL12 uniquely affects tubulin PTMs by promoting both microtubule lysine acetylation and arginine methylation. Together, this work identifies a novel microtubule regulator and provides insight into the requirements for apical extracellular axoneme formation.
初级纤毛是一种关键的感觉细胞器，由被纤毛膜包裹的轴丝微管构成。在极化上皮细胞中，初级纤毛位于顶端表面，必须将这些微管直接延伸到细胞外空间并保持稳定结构。然而，调节纤毛形成与细胞极化之间的相互作用，以及极化上皮细胞中轴丝微管生长和稳定的因素尚未完全明确。在本研究中，我们发现TTLL12，一种之前未被描述的微管蛋白酪氨酸连接酶样（TTLL）家族成员，定位于初级纤毛的基部，是极化肾上皮细胞中纤毛形成所必需的。我们还表明，TTLL12直接结合α/β-微管蛋白异二聚体，并调节微管动力学、稳定性和翻译后修饰（PTM）。虽然所有其他TTLLs催化谷氨酸或甘氨酸添加到微管C末端尾部，但TTLL12通过促进微管赖氨酸乙酰化和精氨酸甲基化独特地影响微管蛋白PTM。总之，这项工作鉴定出一种新型微管调节剂，并深入了解顶端细胞外轴丝形成的要求。
