Porta, EO; Gao, L; Denny, PW; Steel, PG; Kalesh, K; (2023) Inhibition of HSP90 distinctively modulates the global phosphoproteome of Leishmania mexicana developmental stages. Microbiology Spectrum , 11 (6) , Article e0296023. 10.1128/spectrum.02960-23.

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Abstract

Heat shock protein 90 (HSP90) is an evolutionarily conserved chaperone protein that plays a central role in the folding and maturation of a large array of client proteins. In the unicellular parasite Leishmania, the etiological agent of the neglected tropical disease leishmaniasis, treatment with HSP90 inhibitors leads to differentiationfrom promastigote to amastigote stage, resembling the effectsof established environmental triggers, low pH and heat shock. This indicates a crucial role for HSP90 in the life cycle control of Leishmania. However, the underlying molecular mechanisms remain unknown. Using a combination of treatment with the classical HSP90 inhibitor tanespimycin, phosphoproteome enrichment, and tandem mass tag (TMT) labeling-based quantitative proteomic mass spectrometry (MS), we systematically characterized the perturbing effectof HSP90 inhibition on the global phosphoproteome of Leishmania mexicana across its life cycle stages and showed that the HSP90 inhibition causes substantially distinct molecular effectsin promastigote and amastigote forms.While phosphorylation of HSP90 and its co-chaperone HSP70 was decreased in amastigote, the opposite effectwas observed in promastigotes. Our results showed that kinase activity and microtubule motor activity are highly represented in the negatively affectedphosphoproteins of the promastigotes, whereas ribosomal proteins, protein folding, and proton channel activity are preferentially enriched in the perturbed amastigote phosphoproteome. Additionally, cross-comparison of our results with HSP90 inhibition-affectedRNA-binding proteins showed that RNA helicase domains were distinctively enriched among the upregulated amastigote phosphoproteins. In addition to providing robust identificationand quantificationof 1,833 phosphorylated proteins across three life cycle stages of L. mexicana, this study reveals the dramatically differentways the HSP90 inhibition stress modulates the phosphoproteome of the pathogenic amastigote and provides in-depth insight into the scope of selective molecular targeting in the therapeutically relevant amastigote stage.

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