Rabl2 GTP Hydrolysis Licenses BBSome-mediated Export to Fine-tune Ciliary Signaling

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2020 Nov 26

PMID 33241915

Citations 13

Authors

Shichao Duan

Hao Li

Yirong Zhang

Suming Yang

Yawen Chen

Benhua Qiu

Cheng Huang

Juan Wang

JinSong Li

Xueliang Zhu

Xiumin Yan

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

A polarized multicomponent foundation upholds ciliary central microtubules.

Chen Q, Zhao H, Pan X, Fang C, Qiu B, Guo J J Mol Cell Biol. 2024; 16(8).

PMID: 39165107 PMC: 11781205. DOI: 10.1093/jmcb/mjae031.

The IFT81-IFT74 complex acts as an unconventional RabL2 GTPase-activating protein during intraflagellar transport.

Boegholm N, Petriman N, Loureiro-Lopez M, Wang J, Vela M, Liu B EMBO J. 2023; 42(18):e111807.

PMID: 37606072 PMC: 10505919. DOI: 10.15252/embj.2022111807.

RABL2 promotes the outward transition zone passage of signaling proteins in cilia via ARL3.

Zhang R, Sun W, Liu Y, Zhang E, Fan Z Proc Natl Acad Sci U S A. 2023; 120(34):e2302603120.

PMID: 37579161 PMC: 10450674. DOI: 10.1073/pnas.2302603120.

Organization, functions, and mechanisms of the BBSome in development, ciliopathies, and beyond.

Tian X, Zhao H, Zhou J Elife. 2023; 12.

PMID: 37466224 PMC: 10356136. DOI: 10.7554/eLife.87623.

Primary cilia as dynamic and diverse signalling hubs in development and disease.

Mill P, Christensen S, Pedersen L Nat Rev Genet. 2023; 24(7):421-441.

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