Translational reprogramming in response to accumulating stressors ensures critical threshold levels of Hsp90 for mammalian life

Abstract

The cytosolic molecular chaperone Hsp90 is essential for eukaryotic life. It is involved in multiple branches of proteostasis, and as a molecular capacitor in morphological evolution. Although reduced Hsp90 levels cause phenotypic variations and correlate with aging, whether eukaryotic cells and organisms can tune the basal Hsp90 protein levels to alleviate physiologically accumulated stress is unknown. To begin to explore this question, we investigated whether and how mice adapt to the deletion of three out of four alleles encoding cytosolic Hsp90, one Hsp90β allele being the only remaining one. While the vast majority of such mouse embryos die during gestation, survivors apparently manage to increase their Hsp90β protein to at least wild-type levels. Further mechanistic studies revealed an internal ribosome entry site in the 5'UTR of the Hsp90β mRNA allowing translational reprogramming to compensate for the genetic loss of Hsp90 alleles and in response to stress. We found that the minimum amount of total Hsp90 that is required to support viability of mammalian cells and organisms is 50-70% of what is normally there. Those that fail to maintain a threshold level are subject to accelerated senescence, proteostatic collapse, and ultimately death. Therefore, considering that Hsp90 levels can be reduced ≥100-fold in the unicellular budding yeast, critical threshold levels of Hsp90 have been markedly increased during eukaryotic evolution. The incompressible part of the steady-state levels of Hsp90 may have increased to accommodate the ever-growing complexity of the proteome on the path towards mammals.

Cytosolic Hsp90 Isoform-Specific Functions and Clinical Significance

“…In comparison, the levels of Hsp90α are lower in those tissues. However, in testis, retina, and brain, Hsp90α levels are comparatively higher than Hsp90β, whereas in heart and muscle, Hsp90α is almost absent [ 48 , 49 ]. Indeed, we demonstrated an interesting isoform switch in mouse myoblasts: as they differentiate into myotubes, Hsp90α disappears and only Hsp90β remains [ 50 ] (see also chapter 3.2).…”

“…This suggested that Hsp90β can also be induced when cells are under stress. In a recent study, we observed that Hsp90β expression can be induced by genetic stress as well as by long-term moderate heat stress at the translational level through an IRES in the Hsp90β mRNA [ 49 ]. Other studies also showed that Hsp90β can be induced under heat and nutrient stress [ 67 , 68 ].…”

“…With many studies, it must be kept in mind, though, that it is not easily possible to exclude the possibility that the observed phenotype is due to reduced total Hsp90 levels or activity. Indeed, we know from our own studies that phenotypes can be due to the latter rather than the loss or inhibition of a specific isoform [ 49 ].…”

“…Most of the functions of Hsp90α are thus connected to stress response pathways and proteins. Unlike Hsp90β, Hsp90α is not necessary for viability in the mouse [ 49 , 59 ]. In normal conditions, as discussed above, some organs have a high abundance of Hsp90α, whereas others have negligible expression levels ( ; accessed on 5 August 2022).…”

“…While hsf1 -/- females produce oocytes, they do not carry viable embryos. However, later we showed that no difference in embryo production was observed in female mice lacking Hsp90α compared to the wild-type [ 49 , 59 ]. Hence, it is possible that hsf1 -/- oocytes failed to develop because of some Hsp90α-independent issue.…”