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Vol. 18, Issue 2, 455-463, February 2007

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Misfolded Proteins Traffic from the Endoplasmic Reticulum (ER) Due to ER Export Signals

Division of Cell Biology and Biophysics, School of Biological Sciences, University of Missouri-Kansas City, Kansas City, MO 64110

Submitted August 10, 2006; Revised October 16, 2006; Accepted November 1, 2006
Monitoring Editor: Reid Gilmore

Most misfolded secretory proteins remain in the endoplasmic reticulum (ER) and are degraded by ER-associated degradation (ERAD). However, some misfolded proteins exit the ER and traffic to the Golgi before degradation. Using model misfolded substrates, with or without defined ER exit signals, we found misfolded proteins can depart the ER by continuing to exhibit the functional export signals present in the corresponding correctly folded proteins. Anterograde transport of misfolded proteins utilizes the same machinery responsible for exporting correctly folded proteins. Passive ER retention, in which misfolded proteins fail to exit the ER due to the absence of exit signals or the inability to functionally present them, likely contributes to the retention of nonnative proteins in the ER. Intriguingly, compromising ERAD resulted in increased anterograde trafficking of a misfolded protein with an ER exit signal, suggesting that ERAD and ER exit machinery can compete for binding of misfolded proteins. Disabling ERAD did not result in transport of an ERAD substrate lacking an export signal. This is an important distinction for those seeking possible therapeutic approaches involving inactivating ERAD in anticipation of exporting a partially active protein.

* Present address: Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2080, Australia, 61-2-9295-8238.

Address correspondence to: Antony A. Cooper (a.cooper{at}garvan.org.au)

Abbreviations used: CFS, CPY* luminal domain/Fus1p transmembrane domain/Sys1p cytosolic domain; CFs', CPY* luminal domain/Fus1p transmembrane domain/sys1p (AxA₂₀₀) cytosolic domain; CPY, carboxypeptidase Y; wtCPY, correctly folded carboxypeptidase Y; CPY*, mutant carboxypeptidase Y; ER, endoplasmic reticulum; ERAD, ER-associated degradation; ERQC, ER quality control; gpf, glycosylated pro--factor; wtPrA, correctly folded proteinase A; PrA*, mutant PrA.

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