Abstract

Cellular protein folding is challenged by environmental stress and aging, which lead to aberrant protein conformations and aggregation. One way to antagonize the detrimental consequences of protein misfolding is to reactivate vital proteins from aggregates. In the yeast Saccharomyces cerevisiae, Hsp104 facilitates disaggregation and reactivates aggregated proteins with assistance from Hsp70 (Ssa1) and Hsp40 (Ydj1). The small heat shock proteins, Hsp26 and Hsp42, also function in the recovery of misfolded proteins and prevent aggregation in vitro, but their in vivo roles in protein homeostasis remain elusive. We observed that after a sublethal heat shock, a majority of Hsp26 becomes insoluble. Its return to the soluble state during recovery depends on the presence of Hsp104. Further, cells lacking Hsp26 are impaired in the disaggregation of an easily assayed heat-aggregated reporter protein, luciferase. In vitro, Hsp104, Ssa1, and Ydj1 reactivate luciferase:Hsp26 co-aggregates 20-fold more efficiently than luciferase aggregates alone. Small Hsps also facilitate the Hsp104-mediated solubilization of polyglutamine in yeast. Thus, Hsp26 renders aggregates more accessible to Hsp104/Ssa1/Ydj1. Small Hsps partially suppress toxicity, even in the absence of Hsp104, potentially by sequestering polyglutamine from toxic interactions with other proteins. Hence, Hsp26 plays an important role in pathways that defend cells against environmental stress and the types of protein misfolding seen in neurodegenerative disease.

Highlights

  • Cellular protein folding is challenged by environmental stress and aging, which lead to aberrant protein conformations and aggregation

  • One way to antagonize the detrimental consequences of protein misfolding is to reactivate vital proteins from aggregates

  • Hsp26 plays an important role in pathways that defend cells against environmental stress and the types of protein misfolding seen in neurodegenerative disease

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Summary

Introduction

Cellular protein folding is challenged by environmental stress and aging, which lead to aberrant protein conformations and aggregation. In the yeast Saccharomyces cerevisiae, Hsp104 facilitates disaggregation and reactivates aggregated proteins with assistance from Hsp (Ssa1) and Hsp (Ydj). The small heat shock proteins, Hsp and Hsp, function in the recovery of misfolded proteins and prevent aggregation in vitro, but their in vivo roles in protein homeostasis remain elusive. Members of the sHsp family protect cells from a variety of environmental conditions such as heat and oxidative stress by antagonizing protein aggregation [1,2,3]. Saccharomyces cerevisiae, there are two sHsps, Hsp and Hsp42 Reactivation of aggregated proteins in yeast is carried out by Hsp104 with assistance from the Hsp70/Hsp chaperone system both in vivo and in vitro [12]. The prokaryotic sHsps, IbpA/B, were shown to assist in the reactivation of aggregated substrates by ClpB, Hsp, and Hsp40 [13, 14]

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