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Proteomic data from human cell cultures refine mechanisms of chaperone-mediated protein homeostasis

  • Original Paper
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Cell Stress and Chaperones Aims and scope

Abstract

In the crowded environment of human cells, folding of nascent polypeptides and refolding of stress-unfolded proteins is error prone. Accumulation of cytotoxic misfolded and aggregated species may cause cell death, tissue loss, degenerative conformational diseases, and aging. Nevertheless, young cells effectively express a network of molecular chaperones and folding enzymes, termed here “the chaperome,” which can prevent formation of potentially harmful misfolded protein conformers and use the energy of adenosine triphosphate (ATP) to rehabilitate already formed toxic aggregates into native functional proteins. In an attempt to extend knowledge of chaperome mechanisms in cellular proteostasis, we performed a meta-analysis of human chaperome using high-throughput proteomic data from 11 immortalized human cell lines. Chaperome polypeptides were about 10 % of total protein mass of human cells, half of which were Hsp90s and Hsp70s. Knowledge of cellular concentrations and ratios among chaperome polypeptides provided a novel basis to understand mechanisms by which the Hsp60, Hsp70, Hsp90, and small heat shock proteins (HSPs), in collaboration with cochaperones and folding enzymes, assist de novo protein folding, import polypeptides into organelles, unfold stress-destabilized toxic conformers, and control the conformal activity of native proteins in the crowded environment of the cell. Proteomic data also provided means to distinguish between stable components of chaperone core machineries and dynamic regulatory cochaperones.

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Abbreviations

MDa:

Megadaltons

Pg:

Picogram

ER:

Endoplasmic reticulum

NEF:

Nucleotide exchange factor

Chaperome:

Members of the chaperone cochaperone, and the folding enzymes PDIs and PPIs

PDIs:

Peptidyl disulfide isomerases

PPIs:

Peptidylprolyl isomerases

SILAC:

Stable isotope labeling with amino acids in cell culture

MS:

Mass spectrometry

IBAQ:

Intensity-based absolute quantification

SD:

Standard deviation

Proteostasis:

Protein homeostasis

Proteopathies:

Protein conformational diseases

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Acknowledgments

This work was supported by the Faculty of Biology and Medicine of Lausanne University of Lausanne and by Grant 31003A-140512/1 from the Swiss National Fund.

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Authors and Affiliations

  1. Department of Plant Molecular Biology, University of Lausanne, 1015, Lausanne, Switzerland

    Andrija Finka & Pierre Goloubinoff

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  1. Andrija Finka
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  2. Pierre Goloubinoff
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Correspondence to Pierre Goloubinoff.

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Supplementary Figure 1

Raw polypeptide abundances in 11 imortalized human cell lines. Bar graphs showing high disparity of (A) absolute polypeptide copy numbers per cell and (B) protein concentration, in the 11 different immortalized human cell lines (Geiger et al. 2012). Total polypeptide copy number and SD are from three independent measures. Hatched boxes are 1010 polypeptides and 300 mg/ml per cell as previously reported (Albe et al. 1990). (DOCX 62 kb)

Supplementary Table 1

Numeral proportions of 11,731 polypeptides in 11 immortalized human cell lines and individual polypeptide copy number in HeLa cells. The numeral proportions of polypeptides with a p value less than 0.1 are labeled in bold. The polypeptide average copy numbers and SD in HeLa cells are given in a separate sheet (XLSX 7413 kb)

Supplementary Table 2

Mass proportions of 11,731 polypeptides in 11 immortalized human cell lines and individual polypeptide mass in HeLa cells. The mass proportions of polypeptides with a p value less than 0.1 are labeled in bold. The average mass and SD (in picograms) of each polypeptide in HeLa cells are given in a separate sheet (XLSX 9413 kb)

Supplementary Table 3

List of human 147 chaperome members. Numeral proportions, copy numbers, mass proportions with corresponding p values, and mass of each detected chaperome member in HeLa cells (XLSX 43 kb)

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Finka, A., Goloubinoff, P. Proteomic data from human cell cultures refine mechanisms of chaperone-mediated protein homeostasis. Cell Stress and Chaperones 18, 591–605 (2013). https://doi.org/10.1007/s12192-013-0413-3

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  • DOI: https://doi.org/10.1007/s12192-013-0413-3

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