Meta-analysis of heat- and chemically upregulated chaperone genes in plant and human cells

Abstract

Molecular chaperones are central to cellular protein homeostasis. In mammals, protein misfolding diseases and aging cause inflammation and progressive tissue loss, in correlation with the accumulation of toxic protein aggregates and the defective expression of chaperone genes. Bacteria and non-diseased, non-aged eukaryotic cells effectively respond to heat shock by inducing the accumulation of heat-shock proteins (HSPs), many of which molecular chaperones involved in protein homeostasis, in reducing stress damages and promoting cellular recovery and thermotolerance. We performed a meta-analysis of published microarray data and compared expression profiles of HSP genes from mammalian and plant cells in response to heat or isothermal treatments with drugs. The differences and overlaps between HSP and chaperone genes were analyzed, and expression patterns were clustered and organized in a network. HSPs and chaperones only partly overlapped. Heat-shock induced a subset of chaperones primarily targeted to the cytoplasm and organelles but not to the endoplasmic reticulum, which organized into a network with a central core of Hsp90s, Hsp70s, and sHSPs. Heat was best mimicked by isothermal treatments with Hsp90 inhibitors, whereas less toxic drugs, some of which non-steroidal anti-inflammatory drugs, weakly expressed different subsets of Hsp chaperones. This type of analysis may uncover new HSP-inducing drugs to improve protein homeostasis in misfolding and aging diseases.

Fig. 1

Distribution and expression levels of heat-induced chaperome genes in human and plant. Distribution and fold-expression levels of heat-induced genes in (a) human monocyte leukemia THP-1 cells (37°C–>43°C 1 h and (b) plant Arabidopsis thaliana (23°C–>38°C, 90 min). Microarray probes corresponding to bio-informatically predicted chaperome genes are in black and non-chaperome genes are grey. The microarray data for human and plant sets were extracted from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus under the series accession nos. GSE9916 and GSE16222, respectively

Fig. 2

Clustering of upregulated RNA expression levels in Arabidopsis chaperome under seven abiotic and chemical treatments: dithiothreitol (DTT), tunicamycin, salicylic acid, ibuprofen, 2,3,5- triiodobenzoicacid (TIBA), 2,4,6-trihydroxybenzamide (2,4,6-T), and heat treatment as indicated. Gene clusters typical of (a) the cellular stress response (CSR) or of the (b) unfolded protein response (UPR). The presumed subcellular localizations are indicated with different background colors

Fig. 3

Clustering of upregulated RNA expression levels in the human chaperome under 21 treatments: A 2-deoxyglucose, B tunicamycin, C phorbol 12-myristate 13-acetate, D cadmium, E N-acetylcysteine, F paclitaxel, G doxycycline, H echinomycin, I heat shock study, J elesclomol, K smoking, L simvastatin, M etoposide, N VAF347, O sapphyrin PCI-5002, P propiconazole, Q myclobutanil, R rifampicin, S dihydrotestosterone, T estrogen, and U apple procyanidin. Gene clusters typical a of the cellular stress response (CSR), b of the unfolded protein response (UPR), and c of a main less specific cell response are shown. The presumed subcellular localizations are indicated with different background colors of the gene names

Fig. 4

Expression profile of human Hsp70 and Hsp40 orthologs under different treatments. Heat and UV induced up- and downregulated human Hsp70 and Hsp40 genes, as compared to isothermal treatments with two Hsp90 inhibitors and four different NSAIDs, as indicated

Fig. 5

Chaperone network rearrangements in CSR and UPR. a Interaction network of proteins in different cellular functions from STRING analysis of the chaperome (Supplemental Table 1) showing Hsp70 (green), Hsp90 (magenta), foldases (orange), small Hsp (black) and chaperonin subnetwork (gray). b Stress-induced centralization of chaperone hubs in CSR (red), UPR (orange), or both (pink)

Fig. 6

Heat shock elements found in heat-induced human chaperome genes. Distribution of fold expression levels of heat-induced chaperone genes in human monocyte leukemia THP-1cells (graph) and the presence of specific HSEs between −3000 and 300 bp of the translation start site of each genes (lower panel). The microarray data for the human chaperome subset (Supplemental Table 1a) is as in Fig. 1a