Genome-wide CRISPR Analysis Identifies Substrate-Specific Conjugation Modules in ER-Associated Degradation.
Mol Cell
; 73(2): 377-389.e11, 2019 01 17.
Article
en En
| MEDLINE
| ID: mdl-30581143
ABSTRACT
The ubiquitin proteasome system (UPS) maintains the integrity of the proteome by selectively degrading misfolded or mis-assembled proteins, but the rules that govern how conformationally defective proteins in the secretory pathway are selected from the structurally and topologically diverse constellation of correctly folded membrane and secretory proteins for efficient degradation by cytosolic proteasomes is not well understood. Here, we combine parallel pooled genome-wide CRISPR-Cas9 forward genetic screening with a highly quantitative and sensitive protein turnover assay to discover a previously undescribed collaboration between membrane-embedded cytoplasmic ubiquitin E3 ligases to conjugate heterotypic branched or mixed ubiquitin (Ub) chains on substrates of endoplasmic-reticulum-associated degradation (ERAD). These findings demonstrate that parallel CRISPR analysis can be used to deconvolve highly complex cell biological processes and identify new biochemical pathways in protein quality control.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Complejo de la Endopetidasa Proteasomal
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Estudio de Asociación del Genoma Completo
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Degradación Asociada con el Retículo Endoplásmico
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Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas
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Sistemas CRISPR-Cas
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Proteostasis
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Proteína 9 Asociada a CRISPR
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Humans
Idioma:
En
Revista:
Mol Cell
Asunto de la revista:
BIOLOGIA MOLECULAR
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos