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Abstract
Heat shock proteins (Hsps) are among the most widely distributed and evolutionary conserved proteins. Hsps are essential regulators of diverse constitutive metabolic processes and are markedly upregulated during stress. A 62 kDa Hsp (Hsp60) of Histoplasma capsulatum (Hc) is an immunodominant antigen and the major surface ligand to CR3 receptors on macrophages. However little is known about the function of this protein within the fungus. We characterized Hc Hsp60-protein interactions under different temperature to gain insights of its additional functions oncell wall dynamism, heat stress and pathogenesis. We conducted co-immunoprecipitations with antibodies to Hc Hsp60 using cytoplasmic and cell wall extracts. Interacting proteins were identified by shotgun proteomics. For the cell wall, 84 common interactions were identified among the 3 growth conditions, including proteins involved in heat-shock response, sugar and amino acid/protein metabolism and cell signaling. Unique interactions were found at each temperature [30°C (81 proteins), 37°C (14) and 37/40°C (47)]. There were fewer unique interactions in cytoplasm [30°C (6), 37°C (25) and 37/40°C (39)] and four common interactions, including additional Hsps and other known virulence factors. These results show the complexity of Hsp60 function and provide insights into Hc biology, which may lead to new avenues for the management of histoplasmosis.
Highlights
Heat shock proteins (Hsps) are among the most evolutionary highly conserved proteins across all species [1]
Hsp60, enriched at Histoplasma capsulatum (Hc) cell wall, is the ligand recognized by the integrin CR3 (CD11b/CD18), expressed on the surface of macrophage/monocytes [7,8] through which Hc attaches to and is internalized by the phagocytes
Proteins were divided into groups: amino acid metabolism; protein metabolism and modification; carbohydrate metabolism; lipid, fatty acid and steroid metabolism metabolism; nucleoside, nucleotide and nucleic acid metabolism; cell growth/division; nuclear; cell signaling; cytoskeletal; cell wall architecture; plasma membrane; anti-oxidant; proteasome component; chaperone-like; ribosomal; miscellaneous or unclassified biological process
Summary
Heat shock proteins (Hsps) are among the most evolutionary highly conserved proteins across all species [1]. They are classified according to their relative molecular weight, comprising six major groups: small Hsps, Hsp, Hsp, Hsp, Hsp and Hsp110. The mechanism is regulated by Hsf and involves the Ras-PKA pathway, which is modulated by chaperonins [15]. This fact, in association with the presence of distinct Hsps in the cell wall strongly suggests that these proteins could be recruited to re-organize the fungal surface under stress conditions. Knock-down of innumerous proteins results in the loss of cell wall integrity [16], but there is no information concerning how these proteins interact to each other during cell wall reorganization such as involvement of Hsp
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