Mitra, Pallabi and Deshmukh, Abhijit S. and Choudhury, Chinmayee (2021) Molecular chaperone function of stress inducible Hsp70 is critical for intracellular multiplication of Toxoplasma gondii. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1868 (2). p. 118898. ISSN 01674889

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Abstract

Intracellular pathogens like Toxoplasma gondii often target proteins and pathways critical for host cell survival and stress response. Molecular chaperones encoded by the evolutionary conserved Heat shock proteins (Hsps) maintain proteostasis and are vital to cell survival following exposure to any form of stress. A key protein of this family is Hsp70, an ATP-driven molecular chaperone, which is stress inducible and often indiscernible in normal cells. Role of this protein with respect to intracellular survival and multiplication of protozoan parasite like T. gondii remains to be examined. We find that T. gondii infection upregulates expression of host Hsp70. Hsp70 selective inhibitor 2-phenylethynesulfonamide (PES) attenuates intracellular T. gondii multiplication. Biotinylated PES confirms selective interaction of this small molecule inhibitor with Hsp70. We show that PES acts by disrupting Hsp70 chaperone function which leads to dysregulation of host autophagy. Silencing of host Hsp70 underscores its importance for intracellular multiplication of T. gondii, however, attenuation achieved using PES is not completely attributable to host Hsp70 indicating the presence of other intracellular targets of PES in infected host cells. We find that PES is also able to target T. gondii Hsp70 homologue which was shown using PES binding assay. Detailed molecular docking analysis substantiates PES targeting of TgHsp70 in addition to host Hsp70. While establishing the importance of protein quality control in infection, this study brings to the fore a unique opportunity of dual targeting of host and parasite Hsp70 demonstrating how structural conservation of these proteins may be exploited for therapeutic design.

Item Type:	Article
Subjects:	Animal Genetics and Genomics Infectious Diseases Inflammation Biology Reproductive Biology Genetic Engineering Bioinformatics
Depositing User:	Mr Harjit Singh
Date Deposited:	26 Nov 2020 10:48
Last Modified:	26 Nov 2020 10:48
URI:	http://niab.sciencecentral.in/id/eprint/91

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