ZFIN ID: ZDB-PUB-191115-2
Genome-wide suppressor screen identifies USP35/USP38 as therapeutic candidates for ciliopathies
Tsai, I.C., Adams, K.A., Tzeng, J.A., Shennib, O., Tan, P.L., Katsanis, N.
Date: 2019
Source: JCI insight   4(22): (Journal)
Registered Authors: Katsanis, Nicholas, Tsai, I-Chun
Keywords: Genetic diseases, Genetics, Therapeutics, Ubiquitin-proteosome system
MeSH Terms:
  • Animals
  • Bardet-Biedl Syndrome/drug therapy
  • Bardet-Biedl Syndrome/genetics
  • CRISPR-Cas Systems/genetics
  • Cell Line
  • Cilia/genetics
  • Ciliopathies/genetics*
  • Endopeptidases/genetics*
  • Genetic Techniques
  • Humans
  • Microtubule-Associated Proteins/genetics
  • Phenotype
  • Retinal Degeneration/genetics
  • Ubiquitin-Specific Proteases/genetics*
  • Wnt Signaling Pathway/genetics
  • Zebrafish
  • Zebrafish Proteins/genetics
PubMed: 31723061 Full text @ JCI Insight
The ciliopathies are a group of phenotypically overlapping disorders caused by structural or functional defects in the primary cilium. Although disruption of numerous signaling pathways and cellular trafficking events have been implicated in ciliary pathology, treatment options for affected individuals remain limited. Here, we performed a genome-wide RNAi (RNA interference) screen to identify genetic suppressors of BBS4, one of the genes mutated in Bardet-Biedl syndrome (BBS). We discovered 10 genes that, when silenced, ameliorate BBS4-dependent pathology. One of these encodes USP35, a negative regulator of the ubiquitin proteasome system, suggesting that inhibition of a deubiquitinase, and subsequent facilitation of the clearance of signaling components, might ameliorate BBS-relevant phenotypes. Testing of this hypothesis in transient and stable zebrafish genetic models showed this posit to be true; suppression or ablation of usp35 ameliorated hallmark ciliopathy defects including impaired convergent extension (CE), renal tubule convolution, and retinal degeneration with concomitant clearance of effectors such as β-catenin and rhodopsin. Together, our findings reinforce a direct link between proteasome-dependent degradation and ciliopathies and suggest that augmentation of this system might offer a rational path to novel therapeutic modalities.