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

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