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Published online 15 July 2002. doi:10.1083/jcb.200204122
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© The Rockefeller University Press, 0021-9525/2002/7/247 $5.00
The Journal of Cell Biology, Volume 158, Number 2, July 22, 2002 247-257

Article

Sequential assistance of molecular chaperones and transient formation of covalent complexes during protein degradation from the ER



Maurizio Molinari1, Carmela Galli1, Verena Piccaluga1, Michel Pieren1 and Paolo Paganetti2

1 Institute for Research in Biomedicine, CH-6500 Bellinzona, Switzerland
2 Nervous System, Novartis Pharma AG, CH-4002 Basel, Switzerland

Address correspondence to Maurizio Molinari, Institute for Research in Biomedicine, Via Vela 6, CH-6500 Bellinzona, Switzerland. Tel.: 41-91-820-0319. Fax: 41-91-820-0302. E-mail: maurizio.molinari{at}irb.unisi.ch

BACE457 is a recently identified pancreatic isoform of human ß-secretase. We report that this membrane glycoprotein and its soluble variant are characterized by inefficient folding in the ER, leading to proteasome-mediated ER-associated degradation (ERAD). Dissection of the degradation process revealed that upon release from calnexin, extensively oxidized BACE457 transiently entered in disulfide-bonded complexes associated with the lumenal chaperones BiP and protein disulfide isomerase (PDI) before unfolding and dislocation into the cytosol for degradation. BACE457 and its lumenal variant accumulated in disulfide-bonded complexes, in the ER lumen, also when protein degradation was inhibited. The complexes were disassembled and the misfolded polypeptides were cleared from the ER upon reactivation of the degradation machinery. Our data offer new insights into the mechanism of ERAD by showing a sequential involvement of the calnexin and BiP/PDI chaperone systems. We report the unexpected transient formation of covalent complexes in the ER lumen during the ERAD process, and we show that PDI participates as an oxidoreductase and a redox-driven chaperone in the preparation of proteins for degradation from the mammalian ER.

Key Words: ER-associated protein degradation; molecular chaperones; oxidoreductases; disulfide-bonded complexes; ß-secretase


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