HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 295/6/C1488    most recent 00450.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Choe, K. P. Articles by Strange, K. Search for Related Content PubMed PubMed Citation Articles by Choe, K. P. Articles by Strange, K.

PROTEIN AND VESICLE TRAFFICKING, CYTOSKELETON

Genome-wide RNAi screen and in vivo protein aggregation reporters identify degradation of damaged proteins as an essential hypertonic stress response

Departments of Anesthesiology and Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee

Submitted 1 September 2008 ; accepted in final form 25 September 2008

The damaging effects of hypertonic stress on cellular proteins are poorly defined, and almost nothing is known about the pathways that detect and repair hypertonicity-induced protein damage. To begin addressing these problems, we screened 19,000 Caenorhabditis elegans genes by RNA interference (RNAi) feeding and identified 40 that are essential for survival during acute hypertonic stress. Half (20 of 40) of these genes encode proteins that function to detect, transport, and degrade damaged proteins, including components of the ubiquitin-proteasome system, endosomal sorting complexes, and lysosomes. High-molecular-weight ubiquitin conjugates increase during hypertonic stress, suggesting a global change in the ubiquitinylation state of endogenous proteins. Using a polyglutamine-containing fluorescent reporter, we demonstrate that cell shrinkage induces rapid protein aggregation in vivo and that many of the genes that are essential for survival during hypertonic stress function to prevent accumulation of aggregated proteins. High levels of urea, a strong protein denaturant, do not cause aggregation, suggesting that factors such as macromolecular crowding also contribute to protein aggregate formation during cell shrinkage. Acclimation of C. elegans to mild hypertonicity dramatically increases the osmotic threshold for protein aggregation, demonstrating that protein aggregation-inhibiting pathways are activated by osmotic stress. Our studies demonstrate that hypertonic stress induces protein damage in vivo and that detection and degradation of damaged proteins are essential mechanisms for survival under hypertonic conditions.

Caenorhabditis elegans; kidney; polyglutamine; macromolecular crowding; cell volume

This article has been cited by other articles:

				M. S. Kwon, S. W. Lim, and H. M. Kwon Hypertonic Stress in the Kidney: A Necessary Evil Physiology, June 1, 2009; 24(3): 186 - 191. [Abstract] [Full Text] [PDF]

				H. M. Kwon Protein misfolding in hypertonic stress: new insights into an old idea. Focus on "Genome-wide RNAi screen and in vivo protein aggregation reporters identify degradation of damaged protein as an essential hypertonic stress response" Am J Physiol Cell Physiol, December 1, 2008; 295(6): C1474 - C1475. [Full Text] [PDF]