Targeting SUFU-mediated GLI activity alleviates ciliopathic phenotypes
Abstract
Ciliopathies are incurable, pleiotropic diseases that result from defective cilia. Several ciliopathic phenotypes arise from improper processing and activity of GLI transcription factors, yet attempts to rescue these phenotypes by overexpressing activator or repressor GLI isoforms have proven unsuccessful. Here, we demonstrate that modulating SUFU-GLI interactions restores GLI transcriptional activity and rescues ciliopathic phenotypes in vivo. As previous work identified increased accumulation of SUFU in ciliopathic conditions, we hypothesized that exploiting SUFU's epistatic relationship to the cilium could provide a novel therapeutic strategy for ciliopathies. Genetic introduction of either a single null allele (Sufu+/-) or point mutation allele (SufuD159R), which modulates SUFU-GLI binding, into a ciliopathic mouse model revealed that both interventions improved midfacial phenotypes; however, SufuD159R provided a more complete rescue by significantly improving mandibular phenotypes as well. Molecular examination of this genetic modification revealed restored GLI3 binding to DNA, GLI3 interaction with transcriptional cofactors, and GLI3-directed transcription of target genes, collectively driving the rescue of numerous ciliopathic phenotypes. These findings reveal cilium-independent functions for SUFU and establish that modulating SUFU-GLI interactions bypasses the need for ciliary GLI processing. Together, these data provide a promising therapeutic approach for ameliorating ciliopathic pathologies.
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BibTeX
@misc{chang2026targeting,
title = {{Targeting SUFU-mediated GLI activity alleviates ciliopathic phenotypes}},
author = {Ching-Fang Chang and Yanfen Yang and Kari M. Brown and Daniel T. Rasicci and Timothy T. Nguyen and Kevin A. Peterson and Samantha A. Brugmann},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.23.760487},
url = {https://www.biorxiv.org/content/10.64898/2026.10.23.760487v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Targeting SUFU-mediated GLI activity alleviates ciliopathic phenotypes
AU - Ching-Fang Chang
AU - Yanfen Yang
AU - Kari M. Brown
AU - Daniel T. Rasicci
AU - Timothy T. Nguyen
AU - Kevin A. Peterson
AU - Samantha A. Brugmann
PY - 2026
DA - 2026/10/23
PB - bioRxiv
DO - 10.64898/2026.10.23.760487
UR - https://www.biorxiv.org/content/10.64898/2026.10.23.760487v1
AB - Ciliopathies are incurable, pleiotropic diseases that result from defective cilia. Several ciliopathic phenotypes arise from improper processing and activity of GLI transcription factors, yet attempts to rescue these phenotypes by overexpressing activator or repressor GLI isoforms have proven unsuccessful. Here, we demonstrate that modulating SUFU-GLI interactions restores GLI transcriptional activity and rescues ciliopathic phenotypes in vivo. As previous work identified increased accumulation of SUFU in ciliopathic conditions, we hypothesized that exploiting SUFU's epistatic relationship to the cilium could provide a novel therapeutic strategy for ciliopathies. Genetic introduction of either a single null allele (Sufu+/-) or point mutation allele (SufuD159R), which modulates SUFU-GLI binding, into a ciliopathic mouse model revealed that both interventions improved midfacial phenotypes; however, SufuD159R provided a more complete rescue by significantly improving mandibular phenotypes as well. Molecular examination of this genetic modification revealed restored GLI3 binding to DNA, GLI3 interaction with transcriptional cofactors, and GLI3-directed transcription of target genes, collectively driving the rescue of numerous ciliopathic phenotypes. These findings reveal cilium-independent functions for SUFU and establish that modulating SUFU-GLI interactions bypasses the need for ciliary GLI processing. Together, these data provide a promising therapeutic approach for ameliorating ciliopathic pathologies.
SN - 2692-8205
ER -