MAST4 promotes primary ciliary resorption through phosphorylation of Tctex-1.
MAST4 promotes primary ciliary resorption through phosphorylation of Tctex-1.
复制标题
DOI：
10.26508/lsa.202301947
复制
发表时间：
2023-11
影响因子：
4.4
通讯作者：
中科院分区：
文献类型：
--
作者：
纤毛吸收的机制尚不清楚。这项研究揭示了微管相关丝氨酸/苏氨酸激酶家族成员 4 (MAST4) 是一种新型激酶，它通过在 Thr94 及其下游效应子上定位 Tctex-1 的纤毛碱基磷酸化来促进纤毛吸收。初级纤毛经历细胞周期依赖性组装和分解。纤毛动力学失调与几种称为纤毛病的病理状况有关。先前的研究表明，磷酸化 Tctex-1 在睫状体基部 Thr94 (T94) 的定位通过加速肌动蛋白重塑和睫状袋膜内吞作用来关键调节纤毛吸收。在这里，我们发现微管相关丝氨酸/苏氨酸激酶家族成员 4 (MAST4) 位于初级纤毛。抑制 MAST4 可阻断血清诱导的纤毛吸收，而过表达 MAST4 可加速纤毛吸收。 Tctex-1 与 MAST4 的激酶结构域结合，其中 R503 和 D504 残基是 MAST4 介导的纤毛吸收的关键。 MAST4 的敲除或催化失活定点 MAST4 突变体的表达可阻断磷酸-(T94)Tctex-1 的纤毛吸收和纤毛碱基定位。此外，在纤毛吸收过程中，MAST4 是 Cdc42 激活和 Rab5 介导的纤毛周膜内吞作用所必需的。这些结果支持 MAST4 是一种新型激酶，通过调节磷酸-(T94)Tctex-1 的纤毛碱基定位来调节纤毛吸收。 MAST4 是治疗由纤毛吸收缺陷引起的纤毛病的潜在新靶点。
The mechanism that underlies cilium resorption is not well understood. This study reveals the microtubule-associated serine/threonine kinase family member 4 (MAST4) is a novel kinase that promotes ciliary resorption by localizing ciliary base-phosphorylation of Tctex-1 at Thr94 and its downstream effectors. The primary cilium undergoes cell cycle–dependent assembly and disassembly. Dysregulated ciliary dynamics are associated with several pathological conditions called ciliopathies. Previous studies showed that the localization of phosphorylated Tctex-1 at Thr94 (T94) at the ciliary base critically regulates ciliary resorption by accelerating actin remodeling and ciliary pocket membrane endocytosis. Here, we show that microtubule-associated serine/threonine kinase family member 4 (MAST4) is localized at the primary cilium. Suppressing MAST4 blocks serum-induced ciliary resorption, and overexpressing MAST4 accelerates ciliary resorption. Tctex-1 binds to the kinase domain of MAST4, in which the R503 and D504 residues are key to MAST4-mediated ciliary resorption. The ciliary resorption and the ciliary base localization of phospho-(T94)Tctex-1 are blocked by the knockdown of MAST4 or the expression of the catalytic-inactive site-directed MAST4 mutants. Moreover, MAST4 is required for Cdc42 activation and Rab5-mediated periciliary membrane endocytosis during ciliary resorption. These results support that MAST4 is a novel kinase that regulates ciliary resorption by modulating the ciliary base localization of phospho-(T94)Tctex-1. MAST4 is a potential new target for treating ciliopathies causally by ciliary resorption defects.
登录
查看更多内容
影响因子：
3.7
作者：
Beretov J;Wasinger VC;Millar EK;Schwartz P;Graham PH;Li Y
通讯作者：
Li Y
影响因子：
5.3
作者：
FEIG, LA;COOPER, GM
通讯作者：
COOPER, GM
影响因子：
11.4
作者：
Lee, Kyung Ho;Johmura, Yoshikazu;Lee, Kyung S.
通讯作者：
Lee, Kyung S.
影响因子：
5.6
作者：
Shiromizu T;Yuge M;Kasahara K;Yamakawa D;Matsui T;Bessho Y;Inagaki M;Nishimura Y
通讯作者：
Nishimura Y
影响因子：
3.3
作者：
Johnson, AO;Lampson, MA;McGraw, TE
通讯作者：
McGraw, TE