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Reductive stress selectively disrupts collagen homeostasis and modifies growth factor-independent signalling through the MAPK/Akt pathway in human dermal fibroblasts.

Carne, N.A. and Bell, S. and Brown, A.P. and Maatta, A. and Flagler, M.J. and Benham, A.M. (2019) 'Reductive stress selectively disrupts collagen homeostasis and modifies growth factor-independent signalling through the MAPK/Akt pathway in human dermal fibroblasts.', Molecular and cellular proteomics., 18 (6). pp. 1123-1137.

Abstract

Redox stress is a well-known contributor to ageing and diseases in skin. Reductants such as dithiothreitol (DTT) can trigger a stress response by disrupting disulfide bonds. However, the quantitative response of the cellular proteome to reductants has not been explored, particularly in cells such as fibroblasts that produce extracellular matrix proteins. Here, we have used a robust, unbiased, label-free SWATH-MS proteomic approach to quantitate the response of skin fibroblast cells to DTT in the presence or absence of the growth factor PDGF. Of the 4487 proteins identified, only 42 proteins showed a statistically significant change of 2-fold or more with reductive stress. Our proteomics data show that reductive stress results in the loss of a small subset of reductant-sensitive proteins (including the collagens COL1A1/2 and COL3A1, and the myopathy-associated collagens COL6A1/2/3), and the downregulation of targets downstream of the MAPK pathway. We show that a reducing environment alters signalling through the PDGF-associated MAPK/Akt pathways, inducing chronic dephosphorylation of ERK1/2 at Thr202/Tyr204 and phosphorylation of Akt at Ser473 in a growth factor-independent manner. Our data highlights collagens as sentinel molecules for redox stress downstream of MAPK/Akt, and identifies intervention points to modulate the redox environment to target skin diseases and conditions associated with erroneous matrix deposition.

Item Type:Article
Full text:(AM) Accepted Manuscript
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Status:Peer-reviewed
Publisher Web site:https://doi.org/10.1074/mcp.RA118.001140
Publisher statement:This research was originally published in Carne, NA, Bell, S, Brown, AP , Maatta, A, Flagler MJ & Benham AM (2019). Reductive stress selectively disrupts collagen homeostasis and modifies growth factor-independent signalling through the MAPK/Akt pathway in human dermal fibroblasts. Molecular and Cellular Proteomics 18(6): 1123-1137 © the American Society for Biochemistry and Molecular Biology.
Date accepted:19 March 2019
Date deposited:20 March 2019
Date of first online publication:19 March 2019
Date first made open access:No date available

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