Abstract
Redox-mediated signal transduction depends on the enzymatic production of second messengers such as hydrogen peroxide, nitric oxide and hydrogen sulfite, as well as specific, reversible redox modifications of cysteine-residues in proteins. So-called thiol switches induce for instance conformational changes in specific proteins that regulate cellular pathways e.g., cell metabolism, proliferation, migration, gene expression and inflammation. Reduction, oxidation and disulfide isomerization are controlled by oxidoreductases of the thioredoxin family, including thioredoxins, glutaredoxins, peroxiredoxins and protein dsisulfide isomerases. These proteins are located in different cellular compartments, interact with substrates and catalyze specific reactions. Interestingly, some of these proteins are released by cells. Their extracellular functions and generally extracellular redox control have been widely underestimated. Here, we give an insight into extracellular redox signaling, extracellular thiol switches and their regulation by secreted oxidoreductases and thiol-isomerases, a topic whose importance has been scarcely studied so far, likely due to methodological limitations. We focus on the secreted redox proteins and characterized thiol switches in the ectodomains of membrane proteins, such as integrins and the metalloprotease ADAM17, which are among the best-characterized proteins and discuss their underlying mechanisms and biological implications.
Highlights
Redox-mediated signal transduction depends on the enzymatic production of second messengers such as hydrogen peroxide, nitric oxide and hydrogen sulfite, as well as specific, reversible redox modifications of cysteineresidues in proteins
We focus on the secreted redox proteins and characterized thiol switches in the ectodomains of membrane proteins, such as integrins and the metalloprotease ADAM17, which are among the best-characterized proteins and discuss their underlying mechanisms and biological implications
Rapid and specific reactions are ensured by the regulated production of second messengers such as hydrogen peroxide, nitric oxide and hydrogen sulfite
Summary
We and others have shown that different cell types, such as endothelial cells, specialized cells like immune cells, hepatocytes and pancreatic β cells, as well as cancer cells, secrete redox proteins that can be altered in response to changes in the cellular environment and have been linked to different biological functions (Table 1). Extracellular redox molecules are known to affect signal transduction and cellular functions (Jones 2006). They are released by epithelial cells directionally, resulting in different redox environments at their apical and basal cell membranes (Mannery et al 2010). Prx and 2 are released by macrophages via exosomes (Mullen et al 2015) Extracellular functions include their general functions as peroxidases and chaperones, as well as the specific function as damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) by binding and activating the TLR4 receptor, independent of their redox activity. The function of KDELR1 is to transport cargo proteins bearing a KDEL motif, such as the above mentioned PDIs, to the cell surface with a higher preference than ER-resident proteins carrying an HDEL sequence.
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