Unglycosylated clusterin variant accumulates in the endoplasmic reticulum and induces cytotoxicity.

Int J Biochem Cell Biol 2013 Feb 29;45(2):221-31. Epub 2012 Nov 29.

Graduate School, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Clusterin is a stress-responsive and highly glycosylated secretory protein that plays cytoprotective role in most body fluids. In addition to extracellular clusterin, several intracellular clusterin variants that are rather cytotoxic have been recently uncovered under diverse pathological conditions. Although these variants revealed heterogeneity in their glycan modification, its significance in many diseases remains to be validated. Here, we found that clusterin is differentially metabolized by two well-characterized ER stress inducers. Thapsigargin induced retrotranslocation and rapid degradation of clusterin from the endoplasmic reticulum, whereas tunicamycin failed to degrade but rather retained clusterin in the endoplasmic reticulum. Important sorting determinant for these processes proved to be N-glycan moieties that are required for the prevention of terminal misfolding and aggregation of clusterin in the endoplasmic reticulum. This study provides a mechanistic insight into the generation of noble cytotoxic variant of intracellular clusterin and an idea about molecular pathogenesis of diseases associated with chronic endoplasmic reticulum stress, such as neurodegeneration.

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biocel.2012.11.014DOI Listing
February 2013
13 Reads

Publication Analysis

Top Keywords

endoplasmic reticulum
20
clusterin endoplasmic
12
clusterin
8
intracellular clusterin
8
endoplasmic
5
reticulum
5
rapid degradation
4
reticulum sorting
4
retrotranslocation rapid
4
sorting determinant
4
degradation clusterin
4
retained clusterin
4
tunicamycin failed
4
induced retrotranslocation
4
degrade retained
4
reticulum tunicamycin
4
failed degrade
4
stress inducers
4
significance diseases
4
diseases remains
4

Similar Publications