Dissociation from BiP and Retrotranslocation of Unassembled Immunoglobulin Light Chains Are Tightly Coupled to Proteasome Activity

Author:

Chillarón Josep1,Haas Ingrid G.1

Affiliation:

1. Biochemie-Zentrum Heidelberg, D-69120 Heidelberg, Germany

Abstract

Unassembled immunoglobulin light chains expressed by the mouse plasmacytoma cell line NS1 (κNS1) are degraded in vivo with a half-life of 50–60 min in a way that closely resembles endoplasmic reticulum (ER)-associated degradation ( Knittler et al., 1995 ). Here we show that the peptide aldehydes MG132 and PS1 and the specific proteasome inhibitor lactacystin effectively increased the half-life of κNS1, arguing for a proteasome-mediated degradation pathway. Subcellular fractionation and protease protection assays have indicated an ER localization of κNS1 upon proteasome inhibition. This was independently confirmed by the analysis of the folding state of κNS1and size fractionation experiments showing that the immunoglobulin light chain remained bound to the ER chaperone BiP when the activity of the proteasome was blocked. Moreover, kinetic studies performed in lactacystin-treated cells revealed a time-dependent increase in the physical stability of the BiP–κNS1complex, suggesting that additional proteins are present in the older complex. Together, our data support a model for ER-associated degradation in which both the release of a soluble nonglycosylated protein from BiP and its retrotranslocation out of the ER are tightly coupled with proteasome activity.

Publisher

American Society for Cell Biology (ASCB)

Subject

Cell Biology,Molecular Biology

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