Novel extracellular and nuclear caspase-1 and inflammasomes propagate inflammation and regulate gene expression: a comprehensive database mining study. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Wang, Luqiao; Fu, Hangfei; Nanayakkara, Gayani; Li, Yafeng; Shao, Ying; Johnson, Candice; Cheng, Jiali; Yang, William; Yang, Fan; Lavallee, Muriel; Xu, Yanjie; Cheng, Xiaoshu; Xi, Hang; Yi, Jonathan; Yu, Jun; Choi, Eric; Wang, Hong; Yang, Xiaofeng
• Is Part Of: Journal of hematology & oncology. Volume 9:Issue 1(2016)
• Page Start: 1
• Page End: 18
• Publication Date: 2016-12
• Subjects: Caspase-1 -- Trafficking -- Nuclear gene regulation -- Inflammation propagation -- Exosome; Hematology -- Periodicals; Oncology -- Periodicals; Blood -- Diseases -- Periodicals; 616.994
• DOI: 10.1186/s13045-016-0351-5
• Languages: English
• ISSNs: 1756-8722

Abstract

Abstract 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.