Multiple Effects of Trehalose on Protein Folding In Vitro and In Vivo

Abstract

The disaccharide trehalose is produced in large quantities by diverse organisms during a variety of stresses. Trehalose prevents proteins from denaturing at high temperatures in vitro, but its function in stress tolerance in vivo is controversial. We report that trehalose stabilizes proteins in yeast cells during heat shock. Surprisingly, trehalose also suppresses the aggregation of denatured proteins, maintaining them in a partially-folded state from which they can be activated by molecular chaperones. The continued presence of trehalose, however, interferes with refolding, suggesting why it is rapidly hydrolyzed following heat shock. These findings reconcile conflicting reports on the role of trehalose in stress tolerance, provide a novel tool for accessing protein folding intermediates, and define new parameters for modulating stress tolerance and protein aggregation.

Dehydration-induced tps gene transcripts from an anhydrobiotic nematode contain novel spliced leaders and encode atypical GT-20 family proteins

“…An increasingly wide range of functions are attributed to trehalose; for example, it is well known to act as an organic osmolyte in micro-organisms [17,[37][38][39] and it has also been implicated in the cold stress response of E. coli [15]. Heat shock and oxidative stress do not seem to activate tps genes in A. avenae, but this contrasts with the situation in micro-organisms, where trehalose is thought to play a role [13,14,16]. At present, other than a few studies in anhydrobiosis, there is sparse information on trehalose synthesis in nematodes [40].…”

“…cerevisiae), the majority are not; accordingly, in the latter species, the role of trehalose is probably not related to desiccation tolerance. Rather, trehalose might be a general stress molecule, at least in micro-organisms, being linked to multiple stress responses, including those to heat [13,14], cold [15], reactive oxygen species [16] and elevated osmolarity [17].…”

Opposite roles of trehalase activity in heat-shock recovery and heat-shock survival in Saccharomyces cerevisiae

“…This might be mediated by one or more of the three STREs (stress-responsive elements) in the promoter region of the NTH1 gene. According to the current model, during heat shock trehalose protects cellular proteins against denaturation and subsequent aggregation, but inhibits the solubilization of protein aggregates and the refolding of the partially denatured proteins during recovery from heat shock [6]. However, it has been unclear [7] whether Nth1 is important because of its role in trehalose hydrolysis or whether Nth1 displays an additional (e.g.…”

“…This possibility has been supported by recent evidence that high trehalose levels inhibit efficient renaturation of partially unfolded proteins by molecular chaperones like Hsp104 [6]. Although the impaired recovery from heat stress of an nth1∆ mutant is consistent with a requirement for rapid mobilization of trehalose after heat shock, there is no direct evidence that it is the enzymic activity of trehalase, and therefore trehalose mobilization, that is important for heat-stress recovery.…”

Metabolic engineering of Saccharomyces cerevisiae for improvement in stresses tolerance

“…[12][13][14][15] Trehalose, a non-reducing disaccharide, works as an energy source in yeasts, bacteria, fungi, invertebrates, insects and plants. 16,17 Many research demonstrated that the higher trehalose accumulated in the yeast cell the higher tolerance against various environmental stresses, for instance ethanol stress, 18 heat stress, 19 saline stress, 20 and various other environmental stresses. 21,22 In S. cerevisiae, concentration of trehalose is regulated by synthesis enzymes and hydrolysis enzymes.…”