Overexpression of the tumor autocrine motility factor receptor Gp78, a ubiquitin protein ligase, results in increased ubiquitinylation and decreased secretion of apolipoprotein B100 in HepG2 cells

Jun Shan Liang, Tonia Kim, Shengyun Fang, Junji Yamaguchi, Allan M. Weissman, Edward A. Fisher, Henry N. Ginsberg

Research output: Contribution to journalArticlepeer-review

97 Scopus citations

Abstract

Apolipoprotein B100 (apoB) is a large (520-kDa) complex secretory protein; its secretion is regulated post-transcriptionally by several degradation pathways. The best described of these degradative processes is cotranslational ubiquitinylation and proteasomal degradation of nascent apoB, involving the 70- and 90-kDa heat shock proteins and the multiple components of the proteasomal pathway. Ubiquitinylation involves several proteins, including ligases called E3s, that coordinate the covalent binding of ubiquitin to target proteins. The recent discovery that tumor autocrine motility factor receptor, also known as gp78, is an endoplasmic reticulum (ER)-associated E3, raised the possibility that this E3 might be involved in the ER-associated degradation of nascent apoB. In a series of experiments in HepG2 cells, we demonstrated that overexpression of gp78 was sufficient for increased ubiquitinylation and proteasomal degradation of apoB, with reduced secretion of apoB-lipoproteins. This action of gp78 was specific: overexpression of the protein did not affect secretion of either albumin or apolipoprotein Al. Furthermore, over. expression of a cytosolic E3, Itch, had no effect on apoB secretion. Finally, using an in vitro translation system, we demonstrated that gp78 led to increased ubiquitinylation and proteasomal degradation of apoB48. Together, these results indicate that an ER-associated protein, gp78, is a bona fide E3 ligase in the apoB ER-associated degradation pathway.

Original languageEnglish
Pages (from-to)23984-23988
Number of pages5
JournalJournal of Biological Chemistry
Volume278
Issue number26
DOIs
StatePublished - 27 Jul 2003

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