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Genome-wide Analysis using ChIP to Identify Isoform-specific Gene Targets
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Genome-wide CRISPR Analysis Identifies Substrate-Specific Conjugation Modules in ER-Associated Degradation
Dara E Leto1, David W Morgens2, Lichao Zhang3
1Department of Biology, Stanford University, Stanford, CA 94305, USA.
Molecular Cell
|December 25, 2018
Summary
Researchers discovered how the ubiquitin proteasome system (UPS) degrades faulty proteins. A new collaboration between E3 ligases forms specific ubiquitin chains for endoplasmic-reticulum-associated degradation (ERAD).
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- The ubiquitin proteasome system (UPS) is crucial for maintaining proteome integrity by degrading misfolded proteins.
- The mechanisms for selecting defective proteins in the secretory pathway for degradation by cytosolic proteasomes are not fully understood.
Purpose of the Study:
- To elucidate the rules governing the degradation of conformationally defective proteins in the secretory pathway.
- To identify novel components and mechanisms involved in endoplasmic-reticulum-associated degradation (ERAD).
Main Methods:
- Utilized parallel pooled genome-wide CRISPR-Cas9 forward genetic screening.
- Employed a highly quantitative and sensitive protein turnover assay.
Main Results:
- Discovered a previously undescribed collaboration between membrane-embedded cytoplasmic ubiquitin E3 ligases.
- Identified the conjugation of heterotypic branched or mixed ubiquitin (Ub) chains on ERAD substrates.
Conclusions:
- Demonstrated that parallel CRISPR analysis can deconvolve complex cell biological processes.
- Identified new biochemical pathways in protein quality control, specifically within ERAD.
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