Posttranslational modification of the NH2-terminal region of CXCL5 by proteases or peptidylarginine Deiminases (PAD) differently affects its biological activity.
Abstract
Posttranslational modifications, e.g. proteolysis, glycosylation, and citrullination regulate chemokine function, affecting leukocyte migration during inflammatory responses. Here, modification of CXCL5/epithelial cell-derived neutrophil-activating protein-78 (ENA-78) by proteases or peptidylarginine deiminases (PAD) was evaluated. Slow CXCL5(1-78) processing by the myeloid cell marker aminopeptidase N/CD13 into CXCL5(2-78) hardly affected its in vitro activity, but slowed down the activation of CXCL5 by the neutrophil protease cathepsin G. PAD, an enzyme with a potentially important function in autoimmune diseases, site-specifically deiminated Arg(9) in CXCL5 to citrulline, generating [Cit(9)]CXCL5(1-78). Compared with CXCL5(1-78), [Cit(9)]CXCL5(1-78) less efficiently induced intracellular calcium signaling, phosphorylation of extracellular signal-regulated kinase, internalization of CXCR2, and in vitro neutrophil chemotaxis. In contrast, conversion of CXCL5 into the previously reported natural isoform CXCL5(8-78) provided at least 3-fold enhanced biological activity in these tests. Citrullination, but not NH(2)-terminal truncation, reduced the capacity of CXCL5 to up-regulate the expression of the integrin α-chain CD11b on ne...Continue Reading
References
Granulocyte chemotactic protein-2 and related CXC chemokines: from gene regulation to receptor usage
The role of post-transcriptional regulation in chemokine gene expression in inflammation and allergy
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