title: Network analyses reveal pervasive functional regulation between proteases in the human protease web.
abstract: Proteolytic processing is an irreversible posttranslational modification affecting a large portion of the proteome. Protease-cleaved mediators frequently exhibit altered activity, and biological pathways are often regulated by proteolytic processing. Many of these mechanisms have not been appreciated as being protease-dependent, and the potential in unraveling a complex new dimension of biological control is increasingly recognized. Proteases are currently believed to act individually or in isolated cascades. However, conclusive but scattered biochemical evidence indicates broader regulation of proteases by protease and inhibitor interactions. Therefore, to systematically study such interactions, we assembled curated protease cleavage and inhibition data into a global, computational representation, termed the protease web. This revealed that proteases pervasively influence the activity of other proteases directly or by cleaving intermediate proteases or protease inhibitors. The protease web spans four classes of proteases and inhibitors and so links both recently and classically described protease groups and cascades, which can no longer be viewed as operating in isolation in vivo. We demonstrated that this observation, termed reachability, is robust to alterations in the data and will only increase in the future as additional data are added. We further show how subnetworks of the web are operational in 23 different tissues reflecting different phenotypes. We applied our network to develop novel insights into biologically relevant protease interactions using cell-specific proteases of the polymorphonuclear leukocyte as a system. Predictions from the protease web on the activity of matrix metalloproteinase 8 (MMP8) and neutrophil elastase being linked by an inactivating cleavage of serpinA1 by MMP8 were validated and explain perplexing Mmp8-/- versus wild-type polymorphonuclear chemokine cleavages in vivo. Our findings supply systematically derived and validated evidence for the existence of the protease web, a network that affects the activity of most proteases and thereby influences the functional state of the proteome and cell activity.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada; Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada; Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Fortelny
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada; Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Cox
authors.affiliation: Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada; Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Reinhild
authors.initials: R
authors.lastname: Kappelhoff
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada; Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Amanda E
authors.initials: AE
authors.lastname: Starr
authors.affiliation: Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada; Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Philipp F
authors.initials: PF
authors.lastname: Lange
authors.affiliation: Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada; Centre for High Throughput Biology, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Pavlidis
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada; Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada; Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Overall
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D019272:Leukocyte Elastase / Q000235:genetics / Q000378:metabolism; D020784:Matrix Metalloproteinase 8 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000166:cytology / Q000201:enzymology*; D025941:Protein Interaction Mapping; D059748:Proteolysis; D020543:Proteome / Q000235:genetics* / Q000378:metabolism; D040901:Proteomics; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000378:metabolism
chemical_list: D020543:Proteome; C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin; D019272:Leukocyte Elastase; C488762:MMP8 protein, human; D020784:Matrix Metalloproteinase 8