ARL3 mediates BBSome ciliary turnover by promoting its outward movement across the transition zone

Liu, Yanxia; Sun, Wei-Yue; Xue, Bin; Zhang, Rui-Kai; Li, Wenjuan; Xie, Xixian; Fan, Zhen‐Chuan

doi:10.1083/jcb.202111076

Cited by 12 publications

(48 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Either GTP- or GDP-bound state and the N-terminal amphipathic helix are two factors required for Arf-like GTPases to anchor to the membrane (28, 49, 52). To dissect how they affect ARL13 anchoring to the membrane, we expressed ARL13 and its variants harboring the mutation G73L, T33N, or the N-terminal 15 residue deletion (ΔN15) combined with G73L, T33N, or none of them in bacteria (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The copyright holder for this preprint this version posted November 3, 2022. ; https://doi.org/10.1101/2022.11.02.514950 doi: bioRxiv preprint with the PLD-laden BBSome, releasing it to load onto retrograde IFT trains for migrating towards to the ciliary base. Upon migrating to the proximal ciliary region right above the TZ, the PLD-laden BBSome dissociates with retrograde IFT trains and moves across the TZ for ciliary retrieval via the ARL3mediated outward BBSome TZ diffusion pathway (28). During ARL13 GTPase cycle, a ciliary ARL13 GAP is potentially required (?).…”

Section: Data Availabilitymentioning

confidence: 99%

“…IFT22 GTP /BBS3 GTP /BBSome dissociates with one another at the basal bodies, allowing IFT22 GTP and the BBSome to integrate into anterograde IFT trains and BBS3 GTP to anchor to the membrane for diffusing into cilia followed by GTPase cycle (28,54). ARL13 in a GTP-bound state targets to the basal bodies at physiological conditions.…”

Section: Data Availabilitymentioning

confidence: 99%

“…ARL3 and ARL13b also mediate signaling protein export from cilia in a BBSome-dependent manner but via distinct mechanisms. As reflected in Chlamydomonas reinhardtii, ARL3 with the aid of Rab-like 2 (RABL2) small GTPase acting as an ARL3 GEF recruits the PLD-laden BBSome as an ARL3 effector to diffuse through the transition zone (TZ) for ciliary retrieval (28)(29)(30). ARL13, the ARL13b orthologue of humans, instead enables PLD coupling with the BBSome for exporting from cilia via the IFT/BBS system (11).…”

Section: Introductionmentioning

confidence: 99%

“…Since many GPCRs like somatostatin receptor 3 and GPR161 and smoothened (Smo) of hedgehog signaling (Hh) pathway couple with the BBSome for loading onto retrograde IFT trains for ciliary retrieval (31–37), roles of ARL13 and ARL3 in PLD coupling with the BBSome (ARL13) and PLD-laden BBSome diffusion through the TZ for ciliary retrieval (ARL3), respectively, well explain their buildup in certain Arl13b and Arl3 mutant cilia of rodent cells (14, 38–40). If these hold true in humans, mutations in ARL3 and ARL13b genes cause BBS could be satisfactorily explained (11, 28).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Unraveling the Intricate Cargo-BBSome Coupling Mechanism at the Ciliary Tip

Liu

Zhang

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Certain ciliary transmembrane and membrane-tethered signaling proteins migrate from the ciliary tip to base via retrograde intraflagellar transport (IFT), essential for maintaining their ciliary dynamics to enable cells to sense and transduce extracellular stimuli inside the cell. During this process, the BBSome functions as an adaptor between retrograde IFT trains and these signaling protein cargoes. The Arf-like 13 (ARL13) small GTPase resembles ARL6/BBS3 in facilitating these signaling cargoes to couple with the BBSome at the ciliary tip prior to loading onto retrograde IFT trains for transporting towards the ciliary base, while the molecular basis for how this intricate coupling event happens remains elusive. Here, we report that Chlamydomonas ARL13 only in a GTP-bound form (ARL13GTP) anchors to the membrane for diffusing into cilia. Upon entering cilia, ARL13 undergoes GTPase cycle for shuttling between the ciliary membrane (ARL13GTP) and matrix (ARL13GDP). To achieve this goal, the ciliary membrane-anchored BBS3GTP binds and activates the ciliary matrix-residing ARL13GDP as an ARL13 guanine nucleotide exchange factor. At the ciliary tip, ARL13GTP binds and recruits the ciliary matrix-residing and post-remodeled BBSome as an ARL13 effector to anchor to the ciliary membrane. This makes the BBSome spatiotemporally become available for the ciliary membrane-tethered phospholipase D (PLD) to couple with. Afterward, ARL13GTP hydrolyzes GTP for releasing the PLD-laden BBSome to load onto retrograde IFT trains. According to this model, hedgehog signaling defects associated with ARL13b and BBS3 mutations in humans could be satisfactorily explained, providing us a mechanistic understanding behind BBSome-cargo coupling required for proper ciliary signaling.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Data Availabilitymentioning

confidence: 99%

Section: Data Availabilitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Unraveling the Intricate Cargo-BBSome Coupling Mechanism at the Ciliary Tip

Liu

Zhang

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

The Arf family GTPases: Regulation of vesicle biogenesis and beyond

Guan

2023

BioEssays

View full text Add to dashboard Cite

The Arf family proteins are best known for their roles in the vesicle biogenesis. However, they also play fundamental roles in a wide range of cellular regulation besides vesicular trafficking, such as modulation of lipid metabolic enzymes, cytoskeleton remodeling, ciliogenesis, lysosomal, and mitochondrial morphology and functions. Growing studies continue to expand the downstream effector landscape of Arf proteins, especially for the less‐studied members, revealing new biological functions, such as amino acid sensing. Experiments with cutting‐edge technologies and in vivo functional studies in the last decade help to provide a more comprehensive view of Arf family functions. In this review, we summarize the cellular functions that are regulated by at least two different Arf members with an emphasis on those beyond vesicle biogenesis.

show abstract

RABL4/IFT27 in a nucleotide‐independent manner promotes phospholipase D ciliary retrieval via facilitating BBSome reassembly at the ciliary tip

Liu

Zhang

Fan

2023

Journal Cellular Physiology

Self Cite

View full text Add to dashboard Cite

Certain ciliary transmembrane and membrane‐associated signaling proteins export from cilia as intraflagellar transport (IFT) cargoes in a BBSome‐dependent manner. Upon reaching the ciliary tip via anterograde IFT, the BBSome disassembles before being reassembled to form an intact entity for cargo phospholipase D (PLD) coupling. During this BBSome remodeling process, Chlamydomonas Rab‐like 4 GTPase IFT27, by binding its partner IFT25 to form the heterodimeric IFT25/27, is indispensable for BBSome reassembly. Here, we show that IFT27 binds IFT25 in an IFT27 nucleotide‐independent manner. IFT25/27 and the IFT subcomplexes IFT‐A and ‐B are irrelevant for maintaining the stability of one another. GTP‐loading onto IFT27 enhances the IFT25/27 affinity for binding to the IFT‐B subcomplex core IFT‐B1 entity in cytoplasm, while GDP‐bound IFT27 does not prevent IFT25/27 from entering and cycling through cilia by integrating into IFT‐B1. Upon at the ciliary tip, IFT25/27 cycles on and off IFT‐B1 and this process is irrelevant with the nucleotide state of IFT27. During BBSome remodeling at the ciliary tip, IFT25/27 promotes BBSome reassembly independent of IFT27 nucleotide state, making postremodeled BBSomes available for PLD to interact with. Thus, IFT25/27 facilitates BBSome‐dependent PLD export from cilia via controlling availability of intact BBSomes at the ciliary tip, while IFT27 nucleotide state does not participate in this regulatory event.

show abstract

ARL3 mediates BBSome ciliary turnover by promoting its outward movement across the transition zone

Cited by 12 publications

References 70 publications

Unraveling the Intricate Cargo-BBSome Coupling Mechanism at the Ciliary Tip

Unraveling the Intricate Cargo-BBSome Coupling Mechanism at the Ciliary Tip

The Arf family GTPases: Regulation of vesicle biogenesis and beyond

RABL4/IFT27 in a nucleotide‐independent manner promotes phospholipase D ciliary retrieval via facilitating BBSome reassembly at the ciliary tip

Contact Info

Product

Resources

About