The Degradome database: expanding roles of mammalian proteases in life and disease

Since the definition of the degradome as the complete repertoire of proteases in a given organism, the combined effort of numerous laboratories has greatly expanded our knowledge of its roles in biology and pathology. Once the genomic sequences of several important model organisms were made available, we presented the Degradome database containing the curated sets of known protease genes in human, chimpanzee, mouse and rat. Here, we describe the updated Degradome database, featuring 81 new protease genes and 7 new protease families. Notably, in this short time span, the number of known hereditary diseases caused by mutations in protease genes has increased from 77 to 119. This increase reflects the growing interest on the roles of the degradome in multiple diseases, including cancer and ageing. Finally, we have leveraged the widespread adoption of new webtools to provide interactive graphic views that show information about proteases in the global context of the degradome. The Degradome database can be accessed through its web interface at http://degradome.uniovi.es.

[1]  X. Puente,et al.  Human and mouse proteases: a comparative genomic approach , 2003, Nature Reviews Genetics.

[2]  Neil D. Rawlings,et al.  MEROPS: the database of proteolytic enzymes, their substrates and inhibitors , 2013, Nucleic Acids Res..

[3]  C. López-Otín,et al.  The functional and pathologic relevance of autophagy proteases. , 2015, The Journal of clinical investigation.

[4]  T. Misteli,et al.  Progeria: A Paradigm for Translational Medicine , 2014, Cell.

[5]  C. López-Otín,et al.  Protease degradomics: A new challenge for proteomics , 2002, Nature Reviews Molecular Cell Biology.

[6]  M. S. Fernández-García,et al.  Loss of MT1‐MMP causes cell senescence and nuclear defects which can be reversed by retinoic acid , 2015, The EMBO journal.

[7]  J. Joyce,et al.  Pericellular proteolysis in cancer , 2014, Genes & development.

[8]  James C. Whisstock,et al.  Perforin and granzymes: function, dysfunction and human pathology , 2015, Nature Reviews Immunology.

[9]  Gonzalo R. Ordóñez,et al.  The Degradome database: mammalian proteases and diseases of proteolysis , 2008, Nucleic Acids Res..

[10]  S. Jentsch,et al.  DNA-protein crosslink repair: proteases as DNA repair enzymes. , 2015, Trends in biochemical sciences.

[11]  V. Quesada,et al.  Proteolytic systems: constructing degradomes. , 2009, Methods in molecular biology.

[12]  Jing Wang,et al.  MCP-induced protein 1 deubiquitinates TRAF proteins and negatively regulates JNK and NF-κB signaling , 2010, The Journal of experimental medicine.

[13]  N. Belyaev,et al.  Amyloid-clearing proteins and their epigenetic regulation as a therapeutic target in Alzheimer’s disease , 2014, Front. Aging Neurosci..

[14]  Alessandro Vullo,et al.  Ensembl 2015 , 2014, Nucleic Acids Res..

[15]  Khaleel Razak,et al.  A delicate balance: role of MMP-9 in brain development and pathophysiology of neurodevelopmental disorders , 2015, Front. Cell. Neurosci..

[16]  Sarah Boyd,et al.  PMAP: databases for analyzing proteolytic events and pathways , 2008, Nucleic Acids Res..

[17]  C. López-Otín,et al.  A genomic view of the complexity of mammalian proteolytic systems. , 2005, Biochemical Society transactions.

[18]  C. López-Otín,et al.  The regulatory crosstalk between kinases and proteases in cancer , 2010, Nature Reviews Cancer.

[19]  C. López-Otín,et al.  Proteases: Multifunctional Enzymes in Life and Disease* , 2008, Journal of Biological Chemistry.

[20]  C. López-Otín,et al.  New roles for mitochondrial proteases in health, ageing and disease , 2015, Nature Reviews Molecular Cell Biology.

[21]  Tatiana A. Tatusova,et al.  Gene: a gene-centered information resource at NCBI , 2014, Nucleic Acids Res..

[22]  D. Turk,et al.  Protease signalling: the cutting edge , 2012, EMBO Journal.

[23]  B. Barres,et al.  MYRF Is a Membrane-Associated Transcription Factor That Autoproteolytically Cleaves to Directly Activate Myelin Genes , 2013, PLoS biology.

[24]  G. Hong,et al.  Nucleic Acids Research , 2015, Nucleic Acids Research.

[25]  V. Quesada,et al.  Deubiquitinases in cancer: new functions and therapeutic options , 2012, Oncogene.