Paper ID: 77
Institute of Molecular Biology, Academia Sinica (Taiwan)
Heat shock protein 90 (Hsp90) is a molecular chaperone essential for cell viability in all eukaryotic cells. In yeast cells, the whole proteome is influenced profoundly when the Hsp90 activity is reduced. Despite the pivotal role that Hsp90 plays in life, our orthologue replacement assays revealed incompatibility between the Yarrowia lipolytica (Yl) HSP90 and the Saccharomyces cerevisiae genome, suggesting that its interaction network has changed through evolution. To understand how Hsp90 diverged in different species and the underlying driving force, we evolved the Yl-HSP90-carrying S. cerevisiae strain in multiple independent lineages in the normal growth condition (YPD 28°C). After 2,200 generations of evolution, we found that other than improving fitness in the normal condition, different evolved clones gained additional growth advantages in various stress conditions, indicating that they have adapted through different evolutionary trajectories. We sequenced the evolved clones and found that many mutations occurred in Hsp90 clients or client-related proteins. Moreover, several genes involved in protein homeostasis were mutated, suggesting that cells could relieve the Hsp90 defects by enhancing alternative pathways. Bulked segregate analysis was performed in three evolved clones to identify the mutations that have major contributions. In total we identified 10 mutations and confirmed the effect by reconstituting them in ancestral strains. Our results provide the potential explanation for the divergent evolution of Hsp90-interaction network and demonstrate the possible compensatory mutational paths that cells could apply when an essential network is perturbed.