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Genome-wide suppressor screen identifies USP35/USP38 as therapeutic candidates for ciliopathies
I-Chun Tsai, … , Perciliz L. Tan, Nicholas Katsanis
I-Chun Tsai, … , Perciliz L. Tan, Nicholas Katsanis
Published November 14, 2019
Citation Information: JCI Insight. 2019;4(22):e130516. https://doi.org/10.1172/jci.insight.130516.
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Categories: Research Article Genetics Therapeutics

Genome-wide suppressor screen identifies USP35/USP38 as therapeutic candidates for ciliopathies

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Abstract

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.

Authors

I-Chun Tsai, Kevin A. Adams, Joyce A. Tzeng, Omar Shennib, Perciliz L. Tan, Nicholas Katsanis

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Figure 5

Rescue of the ift88 morphant phenotype with cosuppression of usp38 in 5dpf zebrafish larvae.

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Rescue of the ift88 morphant phenotype with cosuppression of usp38 in 5d...
(A) Mislocalization of rhodopsin staining (green) is trapped in the cytoplasm of the outer nuclear layer (ONL) cells in ift88 morphant (arrowheads), but localization is restored to normal in double bbs4/usp38 mutants. Blue, DAPI. Top and bottom panels of images were taken at 20×, and midpanel of images were taken at 40×. (B) The rhodopsin located in the cytoplasmic region (indicated by dashed red line in A) of ONL cells was quantified by ImageJ (NIH). Suppression of ift88 causes a significant increase of rhodopsin mislocalization. Cosuppression of usp38 rescues this defect (1-way ANOVA). **P < 0.01; ****P < 0.0001. (C) Assessment of visual function by visual startle response (VSR). Knockdown of ift88 leads to deficient startle response upon light stimulation. However, the visual ability can be improved by cosuppression of usp38 (1-way ANOVA). ****P < 0.0001.
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