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Novel extracellular and nuclear caspase-1 and inflammasomes propagate inflammation and regulate gene expression: a comprehensive database mining study
Fu, Hangfei Nanayakkara, Gayani Li, Yafeng Johnson, Candice Cheng, Jiali Yang, William Y. Yang, Fan Lavallee, Muriel
Fu, Hangfei
Nanayakkara, Gayani
Li, Yafeng
Johnson, Candice
Cheng, Jiali
Yang, William Y.
Yang, Fan
Lavallee, Muriel
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Journal article
Date
2016-11-14
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Pharmacology
Surgery
Physiology
Surgery
Physiology
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https://doi.org/10.1186/s13045-016-0351-5
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 method s 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.
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Wang, L., Fu, H., Nanayakkara, G. et al. Novel extracellular and nuclear caspase-1 and inflammasomes propagate inflammation and regulate gene expression: a comprehensive database mining study. J Hematol Oncol 9, 122 (2016). https://doi.org/10.1186/s13045-016-0351-5
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BMC
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Journal of Hematology & Oncology, Vol. 9
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