Biology subjects

Sun, W.-Y.

Publications and source records attributed to Sun, W.-Y..

4 recordsLinked to original sources

bioRxiv2026

A split-control criterion for few-shot adaptation in single-cell perturbation prediction

Few-shot adaptation can help or harm single-cell perturbation prediction, but conventional evaluation shares a control estimate between calibration responses and held-out targets. We show how methods carry control error into their predictions and derive its contribution to score inflation. Nested control-depth experiments support inverse-depth scaling of inner-product inflation; correlation inflation also depends on the control noise-to-signal ratio. Independent-control scoring changed the rank of 40 of 52 configuration-dataset entries. We introduce SafeDelta, a split-control criterion that uses calibration data to decide whether to adapt. Across six datasets, mean gated gain was non-negative under the original two-control evaluation. On a deep plate, fixed predictions and decisions retained positive mean gains under three additional independent control references. The same reproducibility principle identified a fibrosis programme that localises to scar in human liver. These results inform adaptation decisions and control-depth planning.

bioinformatics↗

bioRxiv2025

RAB18 Orchestrates Signaling Protein Ciliary Homeostasis by Facilitating BBSome Diffusion through the Transition Zone for Ciliary Entry

The BBSome acts as an intraflagellar transport (IFT) cargo adaptor that connects transmembrane and membrane-anchored signaling proteins to the process of IFT within cilia. This function is critical for ciliary homeostasis maintenance of signaling proteins, allowing for successfully sensing and transducing extracellular stimuli inside the cell. It is established that, upon reaching the proximal ciliary region just above the transition zone (TZ), a diffusion barrier, via retrograde IFT, the BBSome, carrying signaling proteins, disengages from IFT and diffuses through the TZ for ciliary retrieval. This TZ passage event is promoted by the Arf-like 3 GTPase, which utilizes the BBSome autonomously of IFT association as its major effector. While it is known that the intact BBSome is recruited to the basal bodies before entering cilia, the precise mechanism by which it crosses the TZ to access cilia remains elusive. In our study on Chlamydomonas reinhardtii, we disclose that the Ras-associated binding (Rab) GTPase RAB18 is concentrated in a basal body region that overlaps with the BBSome. Positioned at this location, RAB18 in a GTP-bound state (RAB18-GTP) is anchored to the membrane, allowing it to diffuse into cilia. Throughout this process, the BBSome functions as a RAB18 effector, binding to RAB18-GTP and subsequently being recruited to diffuse through the TZ for ciliary entry in an IFT-independent manner. This collaboration between the BBSome and RAB18 is pivotal in maintaining the signaling protein phospholipase D ciliary homeostasis, providing a precise mechanistic understanding of the inward BBSome TZ passage essential for proper ciliary signaling. Significance statementAlthough certain ciliary signaling proteins cross the transition zone (TZ) for ciliary removal via the RABL2-ARL3 module-mediated outward BBSome TZ diffusion pathway, how the BBSome passes the TZ for ciliary entry remains unclear. Here, we show that RAB18, in its GTP-bound state, anchors to the membrane at the basal bodies. As a RAB18 effector, the BBSome is recruited to cross the TZ for ciliary entry via lateral transport between plasma and ciliary membranes. Once inside cilia, the BBSome integrates into anterograde IFT trains and subsequently functions as a phospholipase D (PLD) adaptor, ensuring PLD removal from cilia. This study highlights RAB18s pivotal role in facilitating BBSome entry into cilia, unveiling a regulatory mechanism crucial for maintaining ciliary signaling protein homeostasis.

cell biology↗

bioRxiv2022

RABL2 Regulates Ciliation via Controlling IFT-B1 Basal Body Recruitment and ARL3-mediated BBSome Ciliary Retrieval

Highly conserved intraflagellar transport (IFT) trains and certain small GTPases coordinate to direct ciliation and to maintain the ciliary dynamics of signaling molecules via the IFT cargo adaptor BBSome. Unlike murine Rab-like 2 (RABL2) GTPase that enters cilia to drive outward transition zone (TZ) passage of the BBSome, human orthologue fails to enter cilia but resides at the ciliary base, indispensable for ciliation. However, mechanisms underlying how RABL2 regulates ciliation and BBSome barrier passage remain elusive. Here, we show that Chlamydomonas RABL2 regulates basal body targeting of the IFT-B1 subcomplex component of IFT trains as a RABL2-specific effector, mediating ciliation via controlling IFT-B1 basal body amount available for assembling anterograde IFT trains. RABL2GTP binds IFT-B1 to perform IFT; sheds from retrograde IFT trains at the proximal ciliary region right above the TZ; and converts to RABL2GDP rapidly. Next, RABL2GDP activates the ciliary membrane anchored Arf-like 3 (ARL3) GTPase (ARL3GDP) as a ARL3-specific guanine nucleotide exchange factor. Upon detaching from the ciliary membrane, the active ARL3GTP recruits its BBSome effector, autonomous of retrograde IFT train association, to move cross the TZ for ciliary retrieval. This ensures proper BBSome ciliary turnover for maintaining phototactic response of Chlamydomonas cells. For finishing RABL2 ciliary cycle, RABL2GDP passes the TZ for ciliary retrieval by loading onto the ARL3GTP/BBSome as a BBSome cargo. Our data thus propose that RABL2 mediates ciliation and BBSome ciliary retrieval simultaneously but via distinct molecular pathways. Significance statementIntraflagellar transport (IFT) and its cargo adaptor BBSome are indispensable for ciliation and ciliary singling. Rab-like 2 (RABL2) GTPase mediates ciliation and outward transition zone (TZ) passage of BBSomes with mechanisms yet to be determined. Here, we report that RABL2 decides ciliation by controlling the basal body amount of its effector IFT-B1 available for the assembly of anterograde IFT trains. RABL2GTP cycles through cilia as an IFT-B1 cargo; sheds from IFT at the ciliary base; and undergoes nucleotide exchange for activating ARL3 as an ARL3-specfic guanine nucleotide exchange factor. ARLGTP recruits IFT-shed BBSomes to pass the TZ for ciliary retrieval. RABL2GDP exists cilia via ARL3GTP/BBSome as a BBSome cargo. Therefore, RABL2 functions both outside and inside cilia for initiating IFT and BBSome ciliary retrieval, respectively.

cell biology↗

bioRxiv2021

ARL3 Mediates BBSome Ciliary Turnover by Promoting Its Outward Diffusion through the Transition Zone

Ciliary receptors and their certain downstream signaling components undergo intraflagellar transport (IFT) as BBSome cargoes to maintain their ciliary dynamics for sensing and transducing extracellular stimuli inside the cell. Cargo laden BBSomes shed from retrograde IFT at the proximal ciliary region above the transition zone (TZ) followed by diffusing through the TZ for ciliary retrieval, while how the BBSome barrier passage is controlled remains elusive. Here, we show that the BBSome is a major effector of the Arf-like 3 (ARL3) GTPase in Chlamydomonas. Under physiological condition, ARL3GDP binds the membrane for diffusing into and residing in cilia. Following a nucleotide conversion, ARL3GTP dissociates with the ciliary membrane and binds and recruits the IFT-detached and cargo (phospholipase D, PLD)-laden BBSome at the proximal ciliary region to diffuse through the TZ and out of cilia. ARL3 deficiency impairs ciliary signaling, e.g. phototaxis of Chlamydomonas cells, by disrupting BBSome ciliary retrieval, providing a mechanistic understanding behind BBSome ciliary turnover required for ciliary signaling.

cell biology↗