Interactions between TULP3 tubby domain and ARL13B amphipathic helix promote lipidated protein transport to cilia.
Interactions between TULP3 tubby domain and ARL13B amphipathic helix promote lipidated protein transport to cilia.
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DOI：
10.1091/mbc.e22-10-0473
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发表时间：
2023-03-01
影响因子：
3.3
通讯作者：
Mukhopadhyay, Saikat
中科院分区：
文献类型：
--
作者：
Palicharla, Vivek Reddy;Hwang, Sun-Hee;Somatilaka, Bandarigoda N.;Legue, Emilie;Shimada, Issei S.;Familiari, Nicole E.;Tran, Vanna M.;Woodruff, Jeffrey B.;Liem, Karel F.;Mukhopadhyay, Saikat
初级纤毛是细胞信号传导的纽带，并依赖于特定的蛋白质运输功能。Tubby家族蛋白质TULP 3通过与鞭毛内转运复合物-A（IFT-A）和磷酸肌醇相互作用将完整的膜蛋白转运到纤毛中。先前表明，称为纤毛定位序列（CLS）的短基序对于跨膜货物的TULP 3依赖性纤毛运输是必要的和足够的。然而，TULP 3调节非整合的膜相关蛋白的纤毛区室化的机制以及这种运输是否需要TULP 3依赖性CLS尚不清楚。在这里，我们表明，TULP 3是所需的睫状运输的Joubert综合征相关的棕榈酰化GTCLARL 13 B通过CLS。在ARL 13 B的GT3结构域之前的N-末端两亲性螺旋与TULP 3 tubby结构域偶联用于纤毛运输，与棕榈酰化无关。ARL 13 B转运需要TULP 3与IFT-A结合，但不与磷酸肌醇结合，这表明强的近膜相互作用，不像跨膜货物转运需要TULP 3的两种性质。ARL 13 B的TULP 3介导的运输还调节ARL 13 B的法尼基化和肉豆蔻酰化下游效应物的纤毛富集。脂质化的货物显示出独特的消耗动力学从肾上皮纤毛与Tulp 3缺失诱导的肾脏囊肿形成。总的来说，这些研究结果表明，扩大的作用的tubby域在捕获类似的螺旋二级结构基序从不同的货物。
The primary cilium is a nexus for cell signaling and relies on specific protein trafficking for function. The tubby family protein TULP3 transports integral membrane proteins into cilia through interactions with the intraflagellar transport complex-A (IFT-A) and phosphoinositides. It was previously shown that short motifs called ciliary localization sequences (CLSs) are necessary and sufficient for TULP3-dependent ciliary trafficking of transmembrane cargoes. However, the mechanisms by which TULP3 regulates ciliary compartmentalization of nonintegral, membrane-associated proteins and whether such trafficking requires TULP3-dependent CLSs is unknown. Here we show that TULP3 is required for ciliary transport of the Joubert syndrome–linked palmitoylated GTPase ARL13B through a CLS. An N-terminal amphipathic helix, preceding the GTPase domain of ARL13B, couples with the TULP3 tubby domain for ciliary trafficking, irrespective of palmitoylation. ARL13B transport requires TULP3 binding to IFT-A but not to phosphoinositides, indicating strong membrane-proximate interactions, unlike transmembrane cargo transport requiring both properties of TULP3. TULP3-mediated trafficking of ARL13B also regulates ciliary enrichment of farnesylated and myristoylated downstream effectors of ARL13B. The lipidated cargoes show distinctive depletion kinetics from kidney epithelial cilia with relation to Tulp3 deletion–induced renal cystogenesis. Overall, these findings indicate an expanded role of the tubby domain in capturing analogous helical secondary structural motifs from diverse cargoes.
影响因子：
6.8
作者：
Kuang, Lele;Jiang, Yuchao;Chen, Shuxia;Su, Ke;Peng, Rui;Yang, Xueyan;Wang, Hongyan
通讯作者：
Wang, Hongyan