Rabl2 GTP hydrolysis licenses BBSome-mediated export to fine-tune ciliary signaling.

Shichao Duan, Hao Li, Yirong Zhang, Suming Yang, Yawen Chen, Benhua Qiu, Cheng Huang, Juan Wang, Jinsong Li, Xueliang Zhu, Xiumin Yan

The EMBO journal 2021 Jan 15

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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. © 2020 The Authors.

Citation

Shichao Duan, Hao Li, Yirong Zhang, Suming Yang, Yawen Chen, Benhua Qiu, Cheng Huang, Juan Wang, Jinsong Li, Xueliang Zhu, Xiumin Yan. Rabl2 GTP hydrolysis licenses BBSome-mediated export to fine-tune ciliary signaling. The EMBO journal. 2021 Jan 15;40(2):e105499