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Proteolytic processing and inactivation of CCL2/MCP-1 by meprins

Christian Herzog1,2, Randy S Haun1,3, Sudhir V Shah1,2

  • 1Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.

Biochemistry and Biophysics Reports
|September 29, 2017
PubMed

Insights

Metalloendopeptidases meprin A, meprin α, and meprin β process monocyte chemotactic protein 1 (CCL2/MCP-1). Meprin α significantly reduces CCL2/MCP-1 activity by cleaving its N-terminus, impacting immune cell recruitment.

Area of Science:

  • Biochemistry
  • Immunology
  • Proteolysis

Background:

  • Monocyte chemotactic protein 1 (CCL2/MCP-1) is a key chemokine regulating immune cell migration to inflammatory sites.
  • Metalloendopeptidases, including meprins, are implicated in protein processing and immune modulation.

Purpose of the Study:

  • To investigate the processing of CCL2/MCP-1 by meprin A, meprin α, and meprin β.
  • To determine the impact of meprin-mediated cleavage on CCL2/MCP-1 biological activity.

Main Methods:

  • Purification of meprin A from kidney cortex and expression of recombinant meprin α and β.
  • Amino acid sequencing and mass spectrometry to identify cleavage sites on CCL2/MCP-1.
  • Chemotactic migration assays using THP-1 cells to assess the biological activity of cleaved CCL2/MCP-1.

Main Results:

  • Meprin A and meprin α cleaved mouse CCL2/MCP-1 at the N-terminus (Asn6-Ala7 bond), significantly reducing its chemotactic activity.
  • Meprin β cleaved mouse CCL2/MCP-1 at the C-terminus (Ser74-Glu75 bond) but did not affect activity.
  • Meprin α cleaved human CCL2/MCP-1 at the N-terminus, reducing its biological activity, while meprin β had no effect.

Conclusions:

  • Meprin α and meprin β can differentially process CCL2/MCP-1.
  • Meprin α-mediated N-terminal cleavage significantly impairs CCL2/MCP-1 function, suggesting a role in regulating inflammation.
  • These findings highlight the potential involvement of meprins in modulating chemokine activity during inflammatory responses.
Keywords:
ChemokineInflammationMeprin AMeprin αMeprin βMetalloproteinaseMonocyte chemotactic protein 1

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