Novel extracellular and nuclear caspase-1 and inflammasomes propagate inflammation and regulate gene expression: a comprehensive database mining study.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
['Wang|Luqiao|L|', 'Fu|Hangfei|H|', 'Nanayakkara|Gayani|G|', 'Li|Yafeng|Y|', 'Shao|Ying|Y|', 'Johnson|Candice|C|', 'Cheng|Jiali|J|', 'Yang|William Y|WY|', 'Yang|Fan|F|', 'Lavallee|Muriel|M|', 'Xu|Yanjie|Y|', 'Cheng|Xiaoshu|X|', 'Xi|Hang|H|', 'Yi|Jonathan|J|', 'Yu|Jun|J|', 'Choi|Eric T|ET|', 'Wang|Hong|H|', 'Yang|Xiaofeng|X|']
D000818:Animals D020170:Caspase 1 D016923:Cell Death D002467:Cell Nucleus D002843:Chromatin D003324:Coronary Artery Disease D057225:Data Mining D005786:Gene Expression Regulation D006801:Humans D058847:Inflammasomes D007249:Inflammation D015388:Organelles
Caspase-1 Exosome Trafficking Inflammation propagation Nuclear gene regulation