Jump to main content
Jump to site search

Issue 5-6, 2009
Previous Article Next Article

Multidimensional degradomics identifies systemic autoantigens and intracellular matrix proteins as novel gelatinase B/MMP-9 substrates

Author affiliations

Abstract

The action radius of matrix metalloproteinases or MMPs is not restricted to massive extracellular matrix (ECM) degradation, it extends to the proteolysis of numerous secreted and membrane-bound proteins. Although many instances exist in which cells disintegrate, often in conjunction with induction of MMPs, the intracellular MMP substrate repertoire or degradome remains relatively unexplored. We started an unbiased exploration of the proteolytic modification of intracellularproteins by MMPs, using gelatinase B/MMP-9 as a model enzyme. To this end, multidimensional degradomics technology was developed by the integration of broadly available biotechniques. In this way, 100–200 MMP-9 candidate substrates were isolated, of which 69 were identified. Integration of these results with the known biological functions of the substrates revealed many novel MMP-9 substrates from the intracellular matrix (ICM), such as actin, tubulin, gelsolin, moesin, ezrin, Arp2/3 complex subunits, filamin B and stathmin. About 2/3 of the identified candidates were autoantigens described in multiple autoimmune conditions and in cancer (e.g. annexin I, nucleolin, citrate synthase, HMGB1, α-enolase, histidyl-tRNA synthetase, HSP27, HSC70, HSP90, snRNP D3). These findings led to the insight that MMPs and other proteases may have novel (immuno)regulatory properties by the clearance of toxic and immunogenic burdens of abundant ICM proteins released after extensive necrosis. In line with the extracellular processing of organ-specific autoantigens, proteolysis might also assist in the generation of immunodominant ‘neo-epitopes’ from systemic autoantigens. The study of proteolysis of ICM molecules, autoantigens, alarmins and other crucial intracellular molecules may result in the discovery of novel roles for proteolytic modification.

Graphical abstract: Multidimensional degradomics identifies systemic autoantigens and intracellular matrix proteins as novel gelatinase B/MMP-9 substrates

Back to tab navigation

Supplementary files

Publication details

The article was received on 06 Mar 2009, accepted on 29 Apr 2009 and first published on 12 May 2009


Article type: Paper
DOI: 10.1039/B904701H
Citation: Integr. Biol., 2009,1, 404-426

Search articles by author

Spotlight

Advertisements