title: Novel extracellular and nuclear caspase-1 and inflammasomes propagate inflammation and regulate gene expression: a comprehensive database mining study.
abstract: Caspase-1 is present in the cytosol as an inactive zymogen and requires the protein complexes named "inflammasomes" for proteolytic activation. However, it remains unclear whether the proteolytic activity of caspase-1 is confined only to the cytosol where inflammasomes are assembled to convert inactive pro-caspase-1 to active caspase-1.
  
  
  
  We conducted meticulous data analysis method﻿s on proteomic, protein interaction, protein intracellular localization, and gene expressions of 114 experimentally identified caspase-1 substrates and 38 caspase-1 interaction proteins in normal physiological conditions and in various pathologies.
  
  
  
  We made the following important findings: (1) Caspase-1 substrates and interaction proteins are localized in various intracellular organelles including nucleus and secreted extracellularly; (2) Caspase-1 may get activated in situ in the nucleus in response to intra-nuclear danger signals; (3) Caspase-1 cleaves its substrates in exocytotic secretory pathways including exosomes to propagate inflammation to neighboring and remote cells; (4) Most of caspase-1 substrates are upregulated in coronary artery disease regardless of their subcellular localization but the majority of metabolic diseases cause no significant expression changes in caspase-1 nuclear substrates; and (5) In coronary artery disease, majority of upregulated caspase-1 extracellular substrate-related pathways are involved in induction of inflammation; and in contrast, upregulated caspase-1 nuclear substrate-related pathways are more involved in regulating cell death and chromatin regulation.
  
  
  
  Our identification of novel caspase-1 trafficking sites, nuclear and extracellular inflammasomes, and extracellular caspase-1-based inflammation propagation model provides a list of targets for the future development of new therapeutics to treat cardiovascular diseases, inflammatory diseases, and inflammatory cancers.
authors.affiliation: Centers for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA.|Department of Cardiovascular Medicine, the Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, Jiangxi, 330006, China.
authors.forename: Luqiao
authors.initials: L
authors.lastname: Wang
authors.affiliation: Centers for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA.
authors.forename: Hangfei
authors.initials: H
authors.lastname: Fu
authors.affiliation: Centers for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA.
authors.forename: Gayani
authors.initials: G
authors.lastname: Nanayakkara
authors.affiliation: Centers for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA.
authors.forename: Yafeng
authors.initials: Y
authors.lastname: Li
authors.affiliation: Centers for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Shao
authors.affiliation: Centers for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA.
authors.forename: Candice
authors.initials: C
authors.lastname: Johnson
authors.affiliation: Centers for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA.
authors.forename: Jiali
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Centers for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA.
authors.forename: William Y
authors.initials: WY
authors.lastname: Yang
authors.affiliation: Centers for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Centers for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA.
authors.forename: Muriel
authors.initials: M
authors.lastname: Lavallee
authors.affiliation: Centers for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA.|Department of Cardiovascular Medicine, the Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, Jiangxi, 330006, China.
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Cardiovascular Medicine, the Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, Jiangxi, 330006, China.
authors.forename: Xiaoshu
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Centers for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA.
authors.forename: Hang
authors.initials: H
authors.lastname: Xi
authors.affiliation: Centers for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Yi
authors.affiliation: Centers for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA.|Department of Pharmacology, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.affiliation: Centers for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA.|Department of Surgery, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA.
authors.forename: Eric T
authors.initials: ET
authors.lastname: Choi
authors.affiliation: Centers for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA.|Department of Pharmacology, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Centers for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA. xfyang@temple.edu.|Cardiovascular Research and Thrombosis Research, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA. xfyang@temple.edu.|Department of Pharmacology, Lewis Katz School of Medicine at Temple University, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA. xfyang@temple.edu.|Department of Physiology, 3500 North Broad Street, MERB-1059, Philadelphia, PA, 19140, USA. xfyang@temple.edu.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Yang
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000378:metabolism* / Q000502:physiology; D016923:Cell Death; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D003324:Coronary Artery Disease / Q000473:pathology; D057225:Data Mining / Q000379:methods*; D005786:Gene Expression Regulation; D006801:Humans; D058847:Inflammasomes / Q000502:physiology*; D007249:Inflammation; D015388:Organelles / Q000378:metabolism
chemical_list: D002843:Chromatin; D058847:Inflammasomes; D020170:Caspase 1
keywords: Caspase-1; Exosome; Inflammation propagation; Nuclear gene regulation; Trafficking