title: Changes in translation rate modulate stress-induced damage of diverse proteins.
abstract: Proteostasis is the maintenance of the proper function of cellular proteins. Hypertonic stress disrupts proteostasis and causes rapid and widespread protein aggregation and misfolding in the nematode Caenorhabditis elegans. Optimal survival in hypertonic environments requires degradation of damaged proteins. Inhibition of protein synthesis occurs in response to diverse environmental stressors and may function in part to minimize stress-induced protein damage. We recently tested this idea directly and demonstrated that translation inhibition by acute exposure to cycloheximide suppresses hypertonicity-induced aggregation of polyglutamine::YFP (Q35::YFP) in body wall muscle cells. In this article, we further characterized the relationship between protein synthesis and hypertonic stress-induced protein damage. We demonstrate that inhibition of translation reduces hypertonic stress-induced formation and growth of Q35::YFP, Q44::YFP, and α-synuclein aggregates; misfolding of paramyosin and ras GTPase; and aggregation of multiple endogenous proteins expressed in diverse cell types. Activation of general control nonderepressible-2 (GCN-2) kinase signaling during hypertonic stress inhibits protein synthesis via phosphorylation of eukaryotic initiation factor-2α (eIF-2α). Inhibition of GCN-2 activation prevents the reduction in translation rate and greatly exacerbates the formation and growth of Q35::YFP aggregates and the aggregation of endogenous proteins. The current studies together with our previous work provide the first direct demonstration that hypertonic stress-induced reduction in protein synthesis minimizes protein aggregation and misfolding. Reduction in translation rate also serves as a signal that activates osmoprotective gene expression. The cellular proteostasis network thus plays a critical role in minimizing hypertonic stress-induced protein damage, in degrading stress-damaged proteins, and in cellular osmosensing and signaling.
authors.affiliation: Boylan Center for Cellular and Molecular Physiology, Mount Desert Island Biological Laboratory, Bar Harbor, Maine.
authors.forename: Heejung
authors.initials: H
authors.lastname: Kim
authors.forename: Kevin
authors.initials: K
authors.lastname: Strange
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D003513:Cycloheximide / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology*; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism; D017510:Protein Folding; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D012462:Saline Solution, Hypertonic / Q000633:toxicity; D015398:Signal Transduction; D013312:Stress, Physiological / Q000502:physiology*
chemical_list: D029742:Caenorhabditis elegans Proteins; D011500:Protein Synthesis Inhibitors; D012462:Saline Solution, Hypertonic; D003513:Cycloheximide
keywords: C. elegans; hypertonic stress; organic osmolytes; osmoregulation