Cellular responses to proteostasis perturbations reveal non-optimal feedback in chaperone networks
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The proteostasis network (PN) comprises a plethora of proteins that are dedicated to aid in protein folding and maintenance; some with overlapping functions. Despite this, there are multiple pathophysiological states associated with depletion of chaperones. This is counter-intuitive, assuming cells have the ability to re-program transcriptional outputs in accordance with its proteostasic limitations. Here, we have used S. cerevisiae to understand how cells respond to different types of proteostasis impairments. We monitored the proteostasis status and transcriptome of single deletions of fourteen different Protein Quality Control (PQC) genes. In most cases, cellular response did not activate proteostasis components or pathways that could either complement the function of the missing PQC gene or restore proteostasis. Over-expression of alternate machineries could restore part of the proteostasis defect in two representative PQC gene deletion strains. We posit that S. cerevisiae inherently lacks the ability to sense and respond optimally to defects in proteostasis caused due to deletion of specific PQC components.
KeywordsChaperones Transcriptomics Epistasis Proteostasis S. cerevisiae
We are grateful to Dr. Mohammed Faruq for aiding us with the Illumina sequencing platform. We thank Dr. Deepak Sharma (affiliated to CSIR-IMTECH) for assistance with reagents. This work was primarily funded by OLP1104 grant by CSIR to KC and partially by the grant YSS/2015/000532 from SERB to KM along with SNU core funding. We thank the HPC facility of CSIR-IGIB, for aiding us with computing resources. AG1 (Asmita), AG2 (Abhilash) and LM thank UGC for their fellowship. MV is grateful to CSIR, SD to SNU-core funding, and DPD to DBT for their fellowships.
AG1 and KC designed the work. KC, KM and DD supervised the work and analysis. Sequencing was done by AG1. LM made the TS mutants of Nat-R. DPD made Mutants of yeGFP. AG1, SD, MV did the yeast experiments. The transcriptomics experiments were done by AG1. Analysis was primarily done by AG2 along with AG1 and KC. AG1 and KC wrote the manuscript with input from all authors. All authors read and approved the final version of the manuscript.
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Conflict of interest
Authors declare no competing interests.
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