Van Sciver Lab
Primary Cilia Biology & Polycystic Kidney Disease
Projects
The Van Sciver Lab has multiple exciting projects!
ARF/ARL GTPase Interactions
The ADP-ribosylation factor (ARF) and ARF-like (ARL) family of small GTPases includes a cilium-enriched branch, which coordinates ciliary assembly, protein trafficking, and signaling. Our lab studies the biochemical and functional relationships within this network, focusing on ARL13B, a GTPase concentrated in the ciliary membrane that also acts as a guanine nucleotide exchange factor (GEF) for a second ARL family member, ARL3. Using structure-guided point mutants that selectively disrupt ARL13B’s GEF activity while preserving its other functions, we dissect how this GTPase-GTPase relay is wired and what downstream effectors it engages. Recent work from the lab (Van Sciver et al., J Am Soc Nephrol, 2026) shows that this ARL13B→ARL3 axis is not merely a trafficking mechanism but an active driver of pathology, linking a single nucleotide-exchange event to disease-relevant cellular outcomes.
Ciliary Drivers of Polycystic Kidney Disease
Polycystic kidney disease (PKD), the leading genetic cause of renal failure, arises when mutations in PKD1 or PKD2 disrupt the ciliary polycystin complex, triggering a cilia-dependent cyst activation (CDCA) pathway whose molecular drivers remain poorly defined. We are working to identify the ciliary components that convert polycystin loss into cyst formation. Using mouse genetics, we showed that loss of the ciliary GTPase ARL13B, or a point mutation that selectively disables its guanine nucleotide exchange activity toward ARL3, suppresses Pkd1-dependent cystogenesis without disrupting ciliary structure, reducing kidney enlargement, fibrosis, and injury markers (Van Sciver et al., J Am Soc Nephrol, 2026). These findings pinpoint a discrete subcellular signaling event – ARL13B-mediated activation of ARL3 within the cilium – as a required step in the CDCA pathway, and we are now extending this work to define its downstream effectors and therapeutic potential.
Ciliary E3 Ligases
Primary cilia depend on tightly regulated protein turnover to maintain their composition and signaling output, and ubiquitination is emerging as a central mechanism controlling this process. We are investigating E3 ubiquitin ligases that localize to the cilium or basal body, asking how they select ciliary substrates, respond to signaling cues, and influence ciliogenesis, cilium disassembly, and the trafficking of proteins into and out of the ciliary compartment. Combining proteomics, targeted mutagenesis, and live imaging in mammalian model systems, we aim to map specific E3 ligase-substrate relationships within the cilium and determine how their dysregulation contributes to ciliopathy phenotypes, including cystic kidney disease. This work extends the lab’s broader interest in the regulatory GTPase and ubiquitin networks that govern ciliary protein homeostasis.