Biology subjects

Sun, S.-N.

Publications and source records attributed to Sun, S.-N..

2 recordsLinked to original sources

bioRxiv2025

RAB23 Modulates Signaling Protein Ciliary Homeostasis through Promoting RAB18-mediated Inward BBSome Transition Zone Passage

As an intraflagellar transport (IFT) cargo adaptor, the BBSome targets the basal body region located just below the transition zone (TZ) before proceeding to cross the TZ for ciliary entry. This process of TZ crossing crucially governs BBSome presence and quantity available for signaling protein coupling within cilia, influencing the dynamic behavior of signaling proteins in cilia by controlling their ciliary removal. Our previous study revealed that the GTPase RAB18 binds to its BBSome effector in the basal bodies right below the TZ and recruits the BBSome to cross the TZ for ciliary entry by lateral transport between the plasma and ciliary membranes. However, the mechanism by which RAB18 is activated to accomplish this function has remained elusive. This study uncovers that, under physiological conditions, Chlamydomonas RAB23 in its GDP-bound state (RAB23-GDP) predominantly localizes to the same basal body region as RAB18-GDP and activates RAB18-GDP as a RAB18-specific guanine nucleotide exchange factor. RAB18-GDP attaches to the membrane and binds to the BBSome. This interaction occurs independently of anterograde IFT association, allowing the BBSome to diffuse through the TZ and enter cilia. Subsequently, RAB23-GDP facilitates its own ciliary entry by binding to the RAB18-GTP/BBSome entity as a BBSome cargo. Our findings establish a model where the BBSome enters cilia through the RAB23-RAB18 module-mediated inward BBSome TZ diffusion pathway. According to this model, hedgehog signaling defects caused by rab23 mutations could induce Carpenter syndrome in humans, providing a mechanistic understanding behind the inward BBSome TZ passage required for proper ciliary signaling. Significance statementCertain ciliary signaling proteins are removed from cilia through the outward BBSome transition zone (TZ) diffusion pathway. The inward BBSome TZ crossing is orchestrated by RAB18. The current study unveils that RAB23 in its GDP-bound state (RAB23-GDP) and RAB18-GDP predominantly localize to the same basal body region located just below the TZ. RAB23-GDP activates RAB18-GDP as a RAB18-specific guanine nucleotide exchange factor. RAB18-GTP subsequently recruits the BBSome as its effector to cross the TZ for ciliary entry. Following this, RAB23-GDP enters cilia as a BBSome cargo. The regulatory interplay between RAB23 and RAB18, with RAB23 promoting inward BBSome TZ crossing via RAB18, establishes a molecular mechanism for the BBSome-dependent retrieval of signaling proteins from cilia.

cell biology↗

bioRxiv2022

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

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. Significance statementCertain signaling proteins export in a BBSome-dependent manner from cilia via retrograde IFT. As IFT cargoes, their coupling with the BBSome is mediated by ARL13 and BBS3. Here, we report that ARL13 in a GTP-bound state binds the membrane for diffusing into cilia followed by running GTPase cycle with BBS3 acting as an ARL13-specific guanine nucleotide exchange factor. ARL13GTP recruits the IFT-shed BBSome as its effector to anchor to the membrane of the ciliary tip, making it spatiotemporally available for the ciliary membrane-tethered PLD to bind. Afterward, ARL13 GTP hydrolysis releases the PLD-laden BBSome for retrograde IFT train loading. ARL13 and BBS3 facilitate the cargo-BBSome coupling in such a way providing a regulatory mechanism for signaling protein export from cilia.

cell biology↗