PUBLICATION

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

Authors
Tsai, I.C., Adams, K.A., Tzeng, J.A., Shennib, O., Tan, P.L., Katsanis, N.
ID
ZDB-PUB-191115-2
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
(all 17)
PubMed
31723061 Full text @ JCI Insight
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.
Genes / Markers
Marker Marker Type Name
bbs4GENEBardet-Biedl syndrome 4
dtx1GENEdeltex 1, E3 ubiquitin ligase
engaseGENEendo-beta-N-acetylglucosaminidase
enpp7.1GENEectonucleotide pyrophosphatase/phosphodiesterase 7, tandem duplicate 1
entpd6GENEectonucleoside triphosphate diphosphohydrolase 6
ift88GENEintraflagellar transport 88 homolog
pitpnm2GENEphosphatidylinositol transfer protein, membrane-associated 2
ptmaaGENEprothymosin alpha a
rtrafGENERNA transcription, translation and transport factor
tdrd12GENEtudor domain containing 12
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Figures
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
AB/EKW + CRISPR2-bbs4standard conditionsDay 4
AB/EKW + CRISPR2-bbs4standard conditionsDay 4
AB/EKW + CRISPR2-bbs4standard conditionsDay 4
AB/EKW + CRISPR2-bbs4standard conditionsDay 5
AB/EKW + CRISPR2-bbs4standard conditionsDay 5
AB/EKW + CRISPR2-bbs4 + CRISPR2-usp38standard conditionsDay 4
AB/EKW + CRISPR2-bbs4 + CRISPR2-usp38standard conditionsDay 4
AB/EKW + CRISPR2-bbs4 + CRISPR2-usp38standard conditionsDay 4
AB/EKW + CRISPR2-bbs4 + CRISPR2-usp38standard conditionsDay 5
AB/EKW + CRISPR2-bbs4 + CRISPR2-usp38standard conditionsDay 5
1 - 10 of 41
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Mutations / Transgenics
No data available
Human Disease / Model
Human Disease Fish Conditions Evidence
ciliopathyTAS
1 - 1 of 1
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Sequence Targeting Reagents
Fish
Antibodies
Name Type Antigen Genes Isotypes Host Organism
Ab5-rhomonoclonalMouse
1 - 1 of 1
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Orthology
Gene Orthology
usp38
1 - 1 of 1
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Engineered Foreign Genes
No data available
Mapping
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Citation
Tsai, I.C., Adams, K.A., Tzeng, J.A., Shennib, O., Tan, P.L., Katsanis, N. (2019) Genome-wide suppressor screen identifies USP35/USP38 as therapeutic candidates for ciliopathies. JCI insight. 4(22):.