Proteasome inhibition induces differential heat shock protein response but not unfolded protein response in HepG2 cells.

Full Abstract

Liver, a central organ responsible for the metabolism of carbohydrates, proteins, and lipoproteins, is exposed to various kinds of physiological, pathological, and environmental stresses. We hypothesized that blockage of proteasome degradation pathway induces heat shock protein (HSP) response and unfolded protein response in the liver cells. In this study, we have characterized cellular responses to proteasome inhibition in HepG2 cells, a well-differentiated human hepatoma cells. We found that proteasome inhibition induced differential response among cytosolic HSPs, that is, increased expression of HSP70, but no change in HSP40, HSC70, and HSP90. However, proteasome inhibition did not induce typical unfolded protein response as indicated by absence of stimulation of GRP78 and GRP94 proteins. Upon proteasome inhibition, inclusion bodies were accumulated, and ubiquitin-conjugated proteins appeared in insoluble fraction, together with HSP40, HSP70, HSC70, and HSP90. After proteasome inhibition, misfolded proteins were increased in the cytosol and in the ER compartment as evaluated by examining ubiquitin-conjugated proteins. However, essentially all ER-associated ubiquitin-conjugated proteins were located on the surface of the ER, which explains why proteasome inhibition does not induce unfolded protein response. In conclusion, proteasome inhibition induces differential HSP response, but not unfolded protein response in HepG2 cells. Our study also suggests that HSPs play important roles in directing proteasomal degradation and protein aggregate formation.

Author information

Author/s: Liao, Wei (W); Li, Xiaoying (X); Mancini, Michael (M); Chan, Lawrence (L);

Affiliation: The Department of Medicine, Division of Endocrinology and Metabolism, University of California San Diego School of Medicine, La Jolla, California 92093-0673, USA wliao(-atsign-)ucsd.edu.

Grants: HL51586 (Agency:NHLBI NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: Journal of cellular biochemistry (J Cell Biochem), published in United States. (Language: eng)

Reference: 2006-Nov; vol 99 (issue 4) : pp 1085-95

Dates: Created 2006/10/31; Completed 2006/12/13; Revised 2007/12/03;

PMID: 16767695, status: MEDLINE (last retrieval date: 2/18/2009, IMS Date: )

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