Division of Nephrology and Hypertension, Department of Internal Medicine, and 2 Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
J Cell Biol. 2010 Jun 14;189(6):1039-51. doi: 10.1083/jcb.200912001. Epub 2010 Jun 7.
Intraflagellar transport (IFT) machinery mediates the bidirectional movement of cargos that are required for the assembly and maintenance of cilia. However, little is known about how IFT is regulated in vivo. In this study, we show that the small guanosine triphosphatase (GTPase) adenosine diphosphate ribosylation factor-like protein 13 (ARL-13) encoded by the Caenorhabditis elegans homologue of the human Joubert syndrome causal gene ARL13B, localizes exclusively to the doublet segment of the cilium. arl-13 mutants have shortened cilia with various ultrastructural deformities and a disrupted association between IFT subcomplexes A and B. Intriguingly, depletion of ARL-3, another ciliary small GTPase, partially suppresses ciliogenesis defects in arl-13 mutants by indirectly restoring binding between IFT subcomplexes A and B. Rescue of arl-13 mutants by ARL-3 depletion is mediated by an HDAC6 deacetylase-dependent pathway. Thus, we propose that two conserved small GTPases, ARL-13 and ARL-3, coordinate to regulate IFT and that perturbing this balance results in cilia deformation.
纤毛内运输（IFT）机制介导了为纤毛的组装和维持所需的货物的双向运动。然而，关于 IFT 如何在体内被调节知之甚少。在这项研究中，我们表明，由人类杰特综合征致病基因 ARL13B 的同源物编码的秀丽隐杆线虫中的小鸟嘌呤核苷酸三磷酸酶（GTPase）ADP 核糖基化因子样蛋白 13（ARL-13）仅定位于纤毛的二联体段。arl-13 突变体的纤毛缩短，具有各种超微结构畸形，并且 IFT 亚复合物 A 和 B 之间的关联被破坏。有趣的是，另一种纤毛小 GTPase ARL-3 的耗竭部分通过间接恢复 IFT 亚复合物 A 和 B 之间的结合来抑制 arl-13 突变体的纤毛发生缺陷。ARL-3 耗竭对 arl-13 突变体的挽救是由 HDAC6 去乙酰化酶依赖性途径介导的。因此，我们提出两个保守的小 GTPases，ARL-13 和 ARL-3，协调调节 IFT，并且扰乱这种平衡会导致纤毛变形。
