TY - JOUR
T1 - Genome-wide suppressor screen identifies USP35/USP38 as therapeutic candidates for ciliopathies
AU - Tsai, I. Chun
AU - Adams, Kevin A.
AU - Tzeng, Joyce A.
AU - Shennib, Omar
AU - Tan, Perciliz L.
AU - Katsanis, Nicholas
N1 - Funding Information:
We thank Erica Davis and John Griffin for reading the manuscript and helpful comments. pLKO.1 TRC cloning vector was a gift from David Root (Addgene plasmid 10878). We are grateful to So Young Kim and all members in Duke Functional Genomics Shared Resource for their hospitality and guidance of RNAi screening. This work was supported by NIH grants R01HD042601, R01GM121317, R01DK072301, and P50DK096415 (NK) and by NRSA fellowship F32DK094578 (ICT). NK is a Distinguished George W. Brumley Professor.
PY - 2019/11/14
Y1 - 2019/11/14
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.130516
DO - 10.1172/jci.insight.130516
M3 - Article
C2 - 31723061
AN - SCOPUS:85077360359
VL - 4
JO - JCI insight
JF - JCI insight
SN - 2379-3708
IS - 22
M1 - e130516
ER -