Natural osmolytes alleviate GRP78 and ATF-4 levels: Corroboration for potential modulators of unfolded protein response.

ABSTRACT

AIMS: Osmolytes are small organic molecules which play a significant role in maintaining functional homeostasis of proteins under extreme hostile stresses. Any imbalance to cell homeostasis leads to Endoplasmic Reticulum stress (ER-stress) to which a set of cellular responses both at transcriptional and translational level are initialed for restoration of cellular homeostasis called Unfolded Protein Response (UPR). In the present study we evaluated the role of Sarcosine, Betaine, Hydroxyectoine and Ectoine as potential modulators of UPR. ER-stress was induced by Tunicamycin, a prototypic experimental ER-stress inducer. MAIN METHODS: The endogenous cellular levels of UPR markers Glucose-Regulated Protein 78 (GRP78) and Activating Transcription Factor-4 (ATF-4) were evaluated in presence and absence of these osmolytes after inducing UPR with tunicamycin. As a prelude to this, IC50 values of these osmolytes were determined by using cell viability assays like MTT and Trypan Blue exclusion assay. KEY FINDINGS: We found that these osmolytes in a dose-dependent manner increased the rate of restoration of homeostasis as was evident by the decreased endogenous levels of GRP78 and ATF-4. SIGNIFICANCE: These natural osmolytes can thus be useful in therapeutic intervention to mitigate the pathophysiological state resulting from ER-stress.