Developmental regulation of synthesis and dimerization of the amyloidogenic protease inhibitor cystatin C in the hematopoietic system
- Author(s)
- Xu, Y; Lindemann, P; Vega-Ramos, J; Zhang, JG; Villadangos, JA;
- Details
- Publication Year 2014-04-04,Volume 289,Issue #14,Page 9730-40
- Journal Title
- Journal of Biological Chemistry
- Publication Type
- Journal Article
- Abstract
- The cysteine protease inhibitor cystatin C is thought to be secreted by most cells and eliminated in the kidneys, so its concentration in plasma is diagnostic of kidney function. Low extracellular cystatin C is linked to pathologic protease activity in cancer, arthritis, atherosclerosis, aortic aneurism, and emphysema. Cystatin C forms non-inhibitory dimers and aggregates by a mechanism known as domain swapping, a property that reportedly protects against Alzheimer disease but can also cause amyloid angiopathy. Despite these clinical associations, little is known about the regulation of cystatin C production, dimerization, and secretion. We show that hematopoietic cells are major contributors to extracellular cystatin C levels in healthy mice. Among these cells, macrophages and dendritic cells (DC) are the predominant producers of cystatin C. Both cell types synthesize monomeric and dimeric cystatin C in vivo, but only secrete monomer. Dimerization occurs co-translationally in the endoplasmic reticulum and is regulated by the levels of reactive oxygen species (ROS) derived from mitochondria. Drugs or stimuli that reduce the intracellular concentration of ROS inhibit cystatin C dimerization. The extracellular concentration of inhibitory cystatin C is thus partly dependent on the abundance of macrophages and DC, and the ROS levels. These results have implications for the diagnostic use of serum cystatin C as a marker of kidney function during inflammatory processes that induce changes in DC or macrophage abundance. They also suggest an important role for macrophages, DC, and ROS in diseases associated with the protease inhibitory activity or amyloidogenic properties of cystatin C.
- Publisher
- American Society for Biochemistry and Molecular Biology
- Research Division(s)
- Cancer And Haematology; Immunology
- Publisher's Version
- https://doi.org/10.1074/jbc.M113.538041
- Terms of Use/Rights Notice
- © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
Creation Date: 2014-05-22 07:46:40
Last Modified: 2015-10-29 09:49:02