End of the road: from the er to the proteasome

Access through your institution Buy or subscribe Approximately one-third of proteins are folded and modified in the endoplasmic reticulum (ER) before transport to their final destinations,

including secreted proteins such as growth factors, and transmembrane proteins such as receptors and channels. Thirty years ago, emerging data indicated that some secretory proteins are

degraded in a pre-Golgi compartment. For example, the ∆F508 mutant form of the polytopic chloride channel cystic fibrosis transmembrane conductance regulator (CFTR), which is the most common

cause of cystic fibrosis, is degraded in the early secretory pathway despite retaining partial functionality. How secretory proteins such as CFTR-∆F508 are degraded was an open question,

even prompting speculation that there might be an unidentified ER-resident protease. In 1995, Ron Kopito and colleagues published a landmark paper that demonstrated that CFTR-∆F508 is

degraded in the cytosol by the ubiquitin-proteasome system (UPS). Using a combination of small-molecule inhibitors of the proteasome and dominant-negative and temperature-sensitive mutants

to disrupt ubiquitination, Ward et al. provided the first evidence that the ubiquitination of CFTR-∆F508 promotes its degradation by the cytosolic 26S proteasome. This surprising discovery

revealed that CFTR-∆F508 is not degraded in the ER but is instead transported from the ER to the cytosol for proteolytic destruction via the UPS. These findings implied the existence of ER

ubiquitination factors and machinery for substrate extraction from the ER to the cytosol. Although a large portion of CFTR is cytosolically exposed for ubiquitination, it soon became evident

that luminal secretory proteins are also degraded by the cytosolic UPS. Together with a series of seminal papers from Randy Hampton, Dieter Wolf, Thomas Sommer, Jeff Brodsky, Hidde Ploegh

and others, the findings of Ward et al. established a foundation for the intricate pathway that we now refer to as ER-associated protein degradation (ERAD). This is a preview of subscription

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* Learn about institutional subscriptions * Read our FAQs * Contact customer support REFERENCES ORIGINAL ARTICLE * Ward, C. L., Omura, S. & Kopito, R. R. Degradation of CFTR by the

ubiquitin-proteasome pathway. _Cell_ 83, 121–127 (1995) Article  CAS  Google Scholar  RELATED ARTICLE * Henning, N. J. et al. Deubiquitinase-targeting chimeras for targeted protein

stabilization. _Nat. Chem. Biol._ 18, 412–421 (2022) Article  CAS  Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Molecular and Cell Biology,

University of California, Berkeley, CA, USA James A. Olzmann * Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, USA James A. Olzmann * Chan

Zuckerberg Biohub, San Francisco, CA, USA James A. Olzmann Authors * James A. Olzmann View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING

AUTHOR Correspondence to James A. Olzmann. ETHICS DECLARATIONS COMPETING INTERESTS J.A.O. is on the scientific advisory board of Vicinitas Therapeutics. RIGHTS AND PERMISSIONS Reprints and

permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Olzmann, J.A. End of the road: from the ER to the proteasome. _Nat Rev Mol Cell Biol_ 23, 520 (2022).

https://doi.org/10.1038/s41580-022-00504-8 Download citation * Published: 07 June 2022 * Issue Date: August 2022 * DOI: https://doi.org/10.1038/s41580-022-00504-8 SHARE THIS ARTICLE Anyone

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