HSP90 Shapes the Consequences of Human Genetic Variation

Abstract

Summary HSP90 acts as a protein-folding buffer that shapes the manifestations of genetic variation in model organisms. Whether HSP90 influences the consequences of mutations in humans, potentially modifying the clinical course of genetic diseases, remains unknown. Mining data for >1,500 disease-causing mutants, we found strong correlation between reduced phenotypic severity and a dominant (HSP90≥HSP70) increase in mutant engagement by HSP90. Examining the cancer predisposition syndrome Fanconi Anemia in depth revealed that mutant FANCA proteins engaged predominantly by HSP70 had severely compromised function. In contrast, the function of less severe mutants was preserved by a dominant increase in HSP90 binding. Reducing HSP90’s buffering capacity with inhibitors or febrile temperatures destabilized HSP90-buffered mutants, exacerbating FA-related chemosensitivities. Strikingly, a compensatory FANCA somatic mutation from an “experiment of nature” in monozygotic twins both prevented anemia and reduced HSP90 binding. These findings provide one plausible mechanism for the variable expressivity and environmental sensitivity of genetic diseases.

A stress response that allows highly mutated eukaryotic cells to survive and proliferate

“…A key component of EMBR is the Hsp90 chaperone and several of its accessory cochaperones. Data from flies (Rutherford and Lindquist, 1998), plants (Queitsch et al, 2002;Sangster et al, 2007;Sangster et al, 2008), yeast (Cowen and Lindquist, 2005;Jarosz and Lindquist, 2010), worms (Burga et al, 2011), Mexican cavefish (Rohner et al, 2013), and most recently humans (Karras et al, 2017) suggests that this chaperone plays a key role in the phenotypic manifestation of genetic variation. In mechanistic terms, Hsp90 can assist in the folding of unstable gain-of-function protein variants, thereby potentiating their immediate phenotypic effect.…”

“…Hsp90 is a highly conserved molecular chaperone that functions with dozens of co-chaperones (Taipale et al, 2010;Taipale et al, 2014) to fold hundreds of client proteins, most of which are key regulators of growth and development. From yeast to humans, Hsp90 can strongly influence the phenotypic effects of genetic and epigenetic variation that naturally arises within populations (Burga et al, 2011;Cowen and Lindquist, 2005;Jarosz, 2016;Jarosz and Lindquist, 2010;Karras et al, 2017;Queitsch et al, 2002;Rohner et al, 2013;Rutherford and Lindquist, 1998;Sangster et al, 2004). Although Hsp90 has been shown to enhance phenotypes derived from some recently accumulated genetic variants Mason et al, 2018), the full effects of this chaperone on recently accumulated mutations have yet to be fully characterized.…”

Balance between mutually exclusive traits shifted by variants of a yeast transcription factor

“…Although Hsp90 broadly buffers the phenotypic consequences of genetic variation, only a handful of Hsp90-dependent variants have been mapped to date, limiting our understanding of their prevalence and biological significance ( 36 , 37 ). As the consequences of human disease mutations increasingly are found to be dependent on Hsp90, deep mutational scanning provides a possible experimental avenue to systematically identify features of Hsp90-dependent variation ( 38 , 39 ). In Ste12, such mutations are rare and position-dependent, consistent with their effects on protein folding.…”

Role of HSP90 in the Regulation of de Novo Purine Biosynthesis

“…This assay platform has provided a more global understanding of how HSP90 promotes cellular protein homeostasis, including more recently a correlation between mutation-driven disease severity and enhanced interaction of the mutant client protein with HSP90. 8,11 …”