Reversible protein aggregation as cytoprotective mechanism against heat stress

Abstract

Temperature fluctuation is one of the most frequent threats to which organisms are exposed in nature. The activation of gene expression programs that trigger the transcription of heat stress-protective genes is the main cellular response to resist high temperatures. In addition, reversible accumulation and compartmentalization of thermosensitive proteins in high-order molecular assemblies are emerging as critical mechanisms to ensure cellular protection upon heat stress. Here, we summarize representative examples of membrane-less intracellular bodies formed upon heat stress in yeasts and human cells and highlight how protein aggregation can be turned into a cytoprotective mechanism.

Fig. 1

Cytoprotective aggregation centers under HS. Schematic representation of different intracellular biomolecular condensates formed in Saccharomyces cerevisiae, Schizosaccharomyces pombe, and human cells at different cellular locations upon HS. A Biomolecular condensates in S. cerevisiae upon HS. SGs and CytoQ encompass different cytoplasmic condensates, which contain non-terminally misfolded proteins mainly destined for refolding after the stress, similar to the INQ formed in the nucleus adjacent to the nucleolus. IPODs, however, are aggregate deposits formed in the cytoplasm adjacent to the vacuole, which accumulate terminally misfolded proteins destined for degradation. B Two types of cytoplasmic condensates have been described in S. pombe; PACs and SGs. PACs form upon mild HS and accumulate non-terminally misfolded proteins whose fate is refolding. PACs have been proposed to constitute the precursors of SGs formed upon more severe stress conditions. In the nucleus, misfolded proteins accumulate at NuRs upon acute HS. NuRs form at the nucleolar region and function as reversible protein sequestering centers. Upon stress relief, NuRs dissolution is linked to the restoration of cell growth. C Upon stress conditions, human cells form different cytoplasmic deposition sites, such as SGs or aggresomes. Aggresomes represent sites of terminal aggregation of damaged proteins whose destiny is degradation by autophagic mechanisms. In the nucleus, human cells protect thermosensitive proteins by their coalescence along with lncRNAs transcribed from ribosomal intergenic spacers in nucleolar structures known as amyloid bodies (ABs). AB are reversible structures and have been shown to promote local nuclear translation during the stress. On the other hand, nSBs are nuclear assemblies of RNA and proteins formed upon HS which function by sequestering transcription-related factors facilitating the HS-induced inhibition of bulk RNA transcription