Cilia of higher animals sense various environmental stimuli. Proper ciliary signaling requires appropriate extent of BBSome‐mediated export of membrane receptors across ciliary barrier transition zone (TZ) through retrograde intraflagellar transport (IFT) machinery. How the barrier passage is controlled, however, remains unknown. Here, we show that small GTPase Rabl2 functions as a molecular switch for the outward TZ passage. Rabl2‐GTP enters cilia by binding to IFT‐B complex. Its GTP hydrolysis enables the outward TZ passage of the BBSome and its cargos with retrograde IFT machinery, whereas its persistent association leads to their shedding from IFT‐B during the passing process and consequently ciliary retention. Rabl2 deficiency or expression of a GTP‐locked mutant impairs the ciliary hedgehog signaling without interfering with ciliation and respectively results in different spectrums of mouse developmental disorders. We propose that the switch role of Rabl2 ensures proper turnover of the BBSome and ciliary membrane receptors to fine‐tune cilia‐dependent signaling for normal embryonic development and organismic homeostasis.

中文翻译：

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Rabl2 GTP 水解许可 BBSome 介导的输出以微调纤毛信号

高等动物的纤毛能感知各种环境刺激。适当的纤毛信号传导需要适当程度的 BBSome 介导的膜受体通过逆行鞭毛内转运 (IFT) 机制跨纤毛屏障过渡区 (TZ) 输出。然而，如何控制屏障通道仍然未知。在这里，我们展示了小 GTPase Rabl2 作为向外 TZ 通道的分子开关。Rabl2-GTP 通过与 IFT-B 复合物结合进入纤毛。它的 GTP 水解使 BBSome 及其货物通过逆行 IFT 机器向外 TZ 通过，而其持续结合导致它们在通过过程中从 IFT-B 脱落并因此导致纤毛滞留。Rabl2GTP 锁定突变体的缺乏或表达会损害纤毛刺猬信号而不干扰纤毛，并分别导致不同谱系的小鼠发育障碍。我们建议 Rabl2 的开关作用确保 BBSome 和纤毛膜受体的正常转换，以微调纤毛依赖性信号，以实现正常胚胎发育和有机体稳态。