DSpace logo

Please use this identifier to cite or link to this item: http://dspace.bits-pilani.ac.in:8080/jspui/handle/123456789/13865
Title: Quantitative Proteomics Reveals that Hsp90 Inhibition Dynamically Regulates Global Protein Synthesis in Leishmania mexicana
Authors: Sundriyal, Sandeep
Keywords: Pharmacy
Heat shock protein 90 (Hsp90)
Bioorthogonal noncanonical amino acid tagging (BONCAT)
Issue Date: May-2021
Publisher: ASM Journals
Abstract: Heat shock protein 90 (Hsp90) is a conserved molecular chaperone responsible for the folding and maturation of nascent proteins. Hsp90 is regarded as a master regulator of protein homeostasis in the cell, and its inhibition affects the functions of a large array of client proteins. The classical Hsp90 inhibitor tanespimycin has shown potent antileishmanial activity. Despite the increasing importance of Hsp90 inhibition in the development of antileishmanial agents, the global effects of these inhibitors on the parasite proteome remain unknown. By combining tanespimycin treatment with bioorthogonal noncanonical amino acid tagging (BONCAT) metabolic labeling and isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomic mass spectrometry, for the first time, we robustly profiled the relative changes in the synthesis of hundreds of parasite proteins as functions of dose and duration of the inhibitor treatment. We showed that Hsp90 inhibition dynamically regulates nascent protein synthesis in Leishmania mexicana, with many chaperones and virulence factors showing inhibitor concentration- and treatment duration-dependent changes in relative expression. Many ribosomal proteins showed a downregulation upon severe Hsp90 inhibition, providing the first protein-level evidence that Hsp90 inhibition affects the protein synthesis capacity of the ribosome in this organism. We also provide an unbiased target validation of tanespimycin in L. mexicana using live parasite photoaffinity labeling with a novel chemical probe and quantitative proteomic mass spectrometry. We showed that the classical Hsp90 inhibitor not only engages with its presumed target, Hsp83-1, in L. mexicana promastigotes but also affects multiple proteins involved in protein synthesis and quality control in the parasite. This study defines the Leishmania parasites’ response to Hsp90 inhibition at the level of nascent global protein synthesis and provides a rich resource for future studies on Leishmania spp. biology and antileishmanial drug development.
URI: https://journals.asm.org/doi/full/10.1128/msystems.00089-21
http://dspace.bits-pilani.ac.in:8080/jspui/xmlui/handle/123456789/13865
Appears in Collections:Department of Pharmacy

Files in This Item:
There are no files associated with this item.


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.