PT  - JOURNAL ARTICLE
AU  - Asmita Ghosh
AU  - Abhilash Gangadharan
AU  - Sarada Das
AU  - Monika Verma
AU  - Debasis Dash
AU  - Koyeli Mapa
AU  - Kausik Chakraborty
TI  - The transcriptome of proteostasis perturbations reveal non-optimal response in chaperone networks
AID  - 10.1101/137349
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 137349
4099  - http://biorxiv.org/content/early/2017/05/13/137349.short
4100  - http://biorxiv.org/content/early/2017/05/13/137349.full
AB  - Protein folding abnormalities are associated with the pathology of many diseases. This is surprising given the plethora of cellular machinery dedicated to aid protein folding. It is thought that cellular response to proteotoxicity is generally sufficient, but may be compromised during pathological conditions. We asked if, in a physiological condition, cells have the ability to re-program transcriptional outputs in accordance with proteostasis demands. We have used S. cerevisiae to understand the response of cells when challenged with different proteostasis impairments, by removing one protein quality control (PQC) gene from the system at a time. Using 14 PQC deletions, we investigated the transcriptional response and find the mutants were unable to upregulate pathways that could complement the function of the missing PQC gene. To our surprise, cells have inherently a limited scope of response that is not optimally tuned; with transcriptomic responses being decorrelated with respect to the sign of their epistasis. We conclude that this non-optimality in proteotoxic response may limit the cellular ability to reroute proteins through alternate and productive machineries resulting in pathological states. We posit that epistasis guided synthetic biology approaches may be helpful in realizing the true potential of the cellular chaperone machinery.