Network analyses reveal pervasive functional regulation between proteases in the human protease web.

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 appreciate...

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Autores principales:	Nikolaus Fortelny, Jennifer H Cox, Reinhild Kappelhoff, Amanda E Starr, Philipp F Lange, Paul Pavlidis, Christopher M Overall
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/6c499b3dfca44b46afedb024015fd05d
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spelling	oai:doaj.org-article:6c499b3dfca44b46afedb024015fd05d2021-11-11T05:37:09ZNetwork analyses reveal pervasive functional regulation between proteases in the human protease web.1544-91731545-788510.1371/journal.pbio.1001869https://doaj.org/article/6c499b3dfca44b46afedb024015fd05d2014-05-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24865846/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Proteolytic 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.Nikolaus FortelnyJennifer H CoxReinhild KappelhoffAmanda E StarrPhilipp F LangePaul PavlidisChristopher M OverallPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 12, Iss 5, p e1001869 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Nikolaus Fortelny Jennifer H Cox Reinhild Kappelhoff Amanda E Starr Philipp F Lange Paul Pavlidis Christopher M Overall Network analyses reveal pervasive functional regulation between proteases in the human protease web.
description	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.
format	article
author	Nikolaus Fortelny Jennifer H Cox Reinhild Kappelhoff Amanda E Starr Philipp F Lange Paul Pavlidis Christopher M Overall
author_facet	Nikolaus Fortelny Jennifer H Cox Reinhild Kappelhoff Amanda E Starr Philipp F Lange Paul Pavlidis Christopher M Overall
author_sort	Nikolaus Fortelny
title	Network analyses reveal pervasive functional regulation between proteases in the human protease web.
title_short	Network analyses reveal pervasive functional regulation between proteases in the human protease web.
title_full	Network analyses reveal pervasive functional regulation between proteases in the human protease web.
title_fullStr	Network analyses reveal pervasive functional regulation between proteases in the human protease web.
title_full_unstemmed	Network analyses reveal pervasive functional regulation between proteases in the human protease web.
title_sort	network analyses reveal pervasive functional regulation between proteases in the human protease web.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/6c499b3dfca44b46afedb024015fd05d
work_keys_str_mv	AT nikolausfortelny networkanalysesrevealpervasivefunctionalregulationbetweenproteasesinthehumanproteaseweb AT jenniferhcox networkanalysesrevealpervasivefunctionalregulationbetweenproteasesinthehumanproteaseweb AT reinhildkappelhoff networkanalysesrevealpervasivefunctionalregulationbetweenproteasesinthehumanproteaseweb AT amandaestarr networkanalysesrevealpervasivefunctionalregulationbetweenproteasesinthehumanproteaseweb AT philippflange networkanalysesrevealpervasivefunctionalregulationbetweenproteasesinthehumanproteaseweb AT paulpavlidis networkanalysesrevealpervasivefunctionalregulationbetweenproteasesinthehumanproteaseweb AT christophermoverall networkanalysesrevealpervasivefunctionalregulationbetweenproteasesinthehumanproteaseweb
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Network analyses reveal pervasive functional regulation between proteases in the human protease web.

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