Understanding organellar protein folding capacities and assessing their pharmacological modulation by small molecules
Authors: Mukund M D Pramanik
Namrata Rastogi
Richa Sharma
Niti Kumar
Balasubramanian Chandramouli
Journal: European Journal of Cell Biology (2018)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Aggregation; HSP90; Misfolding; Pyrazole; Sensors.
Affiliations: Department of Parasitology, CSIR-Central Drug Research Institute, Lucknow 226031, Uttar Pradesh, India., Department of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226031, Uttar Pradesh, India., Scuola Normale Superiore, Piazza dei Cavalieri 7, I-56126 Pisa, Italy; CompuNet, Istituto Italiano di Tecnologia (IIT), Via Morego 30, I-16163 Genova, Italy., Department of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226031, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Delhi, India., Department of Parasitology, CSIR-Central Drug Research Institute, Lucknow 226031, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Delhi, India. Electronic address: .

Abstract:  Dysfunctional organellar protein quality control machinery leads to protein misfolding associated cardiovascular, neurodegenerative, metabolic and secretory disorders. To understand organellar homeostasis, suitable tools are required which can sense changes in their respective protein folding capacity upon exposure to environmental and pharmacological perturbations. Herein, we have assessed protein folding capacity of cellular organelles using a metastable sensor selectively targeted to cytosol, nucleus, mitochondria, endoplasmic reticulum, golgi and peroxisomes. Microscopy and biochemical data revealed that these sensors report both acute and organelle-specific cellular insults. It also provided insights into contrasting refolding capacities of cellular organelles to recover from proteotoxic challenges. Further, we used these metastable sensors to evaluate pharmacological modulation of organellar protein folding capacity by small molecules. We observed pyrazole based scaffolds increased organellar protein folding capacity through upregulation of chaperones, mainly HSP90 and its co-chaperone HOP which coordinate refolding of misfolded/aggregated species. Overall, our data highlights the potential use of organelle-specific metastable sensors to understand protein folding capacity of sub-cellular compartments and assess pharmacological correction of their proteostasis imbalance. This study also provides additional avenue for use of these organelle-specific metastable sensors in drug discovery programs for identification of novel pharmacophores and drug repositioning of promising scaffolds for protein conformational diseases associated with different cellular organelles. 

Retracted: No

PubPeer comments:
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 #1 Thanks alot for pointing this out. One DAPI image got duplicated during assembly of panels for microscopy images. The final figure (with corresponding DAPI image for ER sensor) is attached. As the senior author, I take the responsibility of this mistake. The journal as been informed and corrected figure has been sent to them for publishing corrigendum in EJCB.  ,