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Published 12 April 2004. doi:10.1083/jcb.200309132
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 165, Number 1, 41-52
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Article

 Misfolded proteins are sorted by a sequential checkpoint mechanism of ER quality control

Shilpa Vashist and Davis T.W. Ng

Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802

Address correspondence to Davis T.W. Ng, Dept. of Biochemistry and Molecular Biology, 408 South Frear Laboratory, Pennsylvania State University, University Park, PA 16802. Tel.: (814) 863-5686. Fax: (814) 863-5876. email: dtn1{at}psu.edu

Misfolded proteins retained in the endoplasmic reticulum (ER) are degraded by the ER-associated degradation pathway. The mechanisms used to sort them from correctly folded proteins remain unclear. Analysis of substrates with defined folded and misfolded domains has revealed a system of sequential checkpoints that recognize topologically distinct domains of polypeptides. The first checkpoint examines the cytoplasmic domains of membrane proteins. If a lesion is detected, it is retained statically in the ER and rapidly degraded without regard to the state of its other domains. Proteins passing this test face a second checkpoint that monitors domains localized in the ER lumen. Proteins detected by this pathway are sorted from folded proteins and degraded by a quality control mechanism that requires ER-to-Golgi transport. Although the first checkpoint is obligatorily directed at membrane proteins, the second monitors both soluble and membrane proteins. Our data support a model whereby "properly folded" proteins are defined biologically as survivors that endure a series of distinct checkpoints.

Key Words: ER-associated degradation; misfolded proteins; protein folding; protein trafficking; endoplasmic reticulum

Abbreviations used in this paper: CFTR, cystic fibrosis transmembrane conductance regulator; CPY*, mutant carboxypeptidase Y; CT*, membrane-bound CPY* lacking a cytosolic domain; CTG*, CT* with GFP as its cytosolic domain; Endo H, endoglycosidase H; ERAD, ER-associated degradation; ERAD-C, ERAD-Cytosolic; ERAD-L, ERAD-Luminal; GT, glucosyltransferase; KHN, yeast Kar2p signal sequence fused to the simian virus 5 HA-Neuraminidase ectodomain; KWS, KHN luminal domain/Wsc1p transmembrane domain/Ste6-166p mutant cytosolic domain; KWW, KHN luminal domain/Wsc1p transmembrane domain/Wsc1p cytosolic domain.


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