Road to Ruin: Targeting Proteins for Degradation in the Endoplasmic Reticulum

By Melanie H. Smith, Hidde L. Ploegh, Jonathan S. Weissman. Science, 2011

672 citations recorded by the source corpus.

Some nascent proteins that fold within the endoplasmic reticulum (ER) never reach their native state. Misfolded proteins are removed from the folding machinery, dislocated from the ER into the cytosol, and degraded in a series of pathways collectively referred to as ER-associated degradation (ERAD). Distinct ERAD pathways centered on different E3 ubiquitin ligases survey the range of potential substrates. We now know many of the components of the ERAD machinery and pathways used to detect substrates and target them for degradation. Much less is known about the features used to identify terminally misfolded conformations and the broader role of these pathways in regulating protein half-lives.

Subfields: Cell Biology, Epidemiology

View Paper: https://www.semanticscholar.org/paper/8a86c72235360f216c495f23b580f024f8220828

How researchers see this paper

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In Cell Biology

1. C. Hetz
2. F. Papa
3. B. Gardner
4. Ciara M. Gallagher
5. Peter Walter
6. David Pincus
7. K. Gotthardt
8. R. Kaufman

In Epidemiology

1. F. Papa
2. C. Hetz
3. Peter Walter
4. R. Kaufman
5. Laurie H. Glimcher

Citations in the corpus

• The Unfolded Protein Response and Cell Fate Control. (2017, positive): “Through a process called ER-associated degradation (ERAD), unfolded proteins are returned to the cytosol for subsequent ubiquitylation and degradation by the 26S proteasome (Smith et al., 2011).”
• Proteolysis Targeting Chimeras as Therapeutics and Tools for Biological Discovery (2020, neutral): “Bespoke ligands for ligases localized to these organelles will likely be required to enact PROTAC-mediated degradation in these subcellular locations (Smith et al., 2011).”
• Role of ROS and RNS Sources in Physiological and Pathological Conditions (2016, background): “It is well documented that only properly folded proteins can be exported to the Golgi apparatus for further modification and translocated to their destined sites, while misfolded or incompletely folded proteins are retained in the ER [146].”
• Endoplasmic reticulum stress: molecular mechanism and therapeutic targets (2023, background): “Misfolded proteins produced under stress conditions are then removed from the folding machinery, relocated from the ER into the cytosol, and degraded in the ubiquitin-proteasome via a series of pathways collectively referred to as ER-associated degradation (ERAD).(4,5) However, persistent misfolded ”
• Endoplasmic reticulum stress sensing in the unfolded protein response. (2013, background): “Proteins that do not properly fold within a certain time are targeted for ER-associated degradation (ERAD), which efficiently retro-translocates them from the ER into the cytosol for degradation via the ubiquitin-proteasome system (Smith et al. 2011).”