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Defining human ERAD networks through an integrative mapping strategy

2011; Nature Portfolio; Volume: 14; Issue: 1 Linguagem: Inglês

10.1038/ncb2383

1476-4679

John C. Christianson, James A. Olzmann, Thomas A. Shaler, Mathew E. Sowa, Eric J. Bennett, Caleb M. Richter, Ryan E. Tyler, Ethan J. Greenblatt, J. Wade Harper, Ron R. Kopito,

Lysosomal Storage Disorders Research

Proteins that fail to correctly fold or assemble into oligomeric complexes in the endoplasmic reticulum (ER) are degraded by a ubiquitin- and proteasome-dependent process known as ER-associated degradation (ERAD). Although many individual components of the ERAD system have been identified, how these proteins are organized into a functional network that coordinates recognition, ubiquitylation and dislocation of substrates across the ER membrane is not well understood. We have investigated the functional organization of the mammalian ERAD system using a systems-level strategy that integrates proteomics, functional genomics and the transcriptional response to ER stress. This analysis supports an adaptive organization for the mammalian ERAD machinery and reveals a number of metazoan-specific genes not previously linked to ERAD. Improperly folded proteins are targeted for destruction through the endoplasmic-reticulum-associated degradation pathway (ERAD). Kopito and colleagues present a high-resolution interaction analysis of the ERAD system in combination with functional genomics, and identify new ERAD components.