Developmental regulation of synthesis and dimerization of the amyloidogenic protease inhibitor cystatin C in the hematopoietic system

J Biol Chem. 2014 Apr 4;289(14):9730-40. doi: 10.1074/jbc.M113.538041. Epub 2014 Feb 25.


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.

Keywords: Amyloidosis; Dendritic Cells; Macrophages; Protease Inhibitor; Protein Folding; Reactive Oxygen Species (ROS); Vascular Angiopathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cystatin C / biosynthesis*
  • Cystatin C / genetics
  • Dendritic Cells / cytology
  • Dendritic Cells / metabolism
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism
  • Hematopoiesis / physiology
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / metabolism*
  • Inflammation / genetics
  • Inflammation / metabolism
  • Macrophages / cytology
  • Macrophages / metabolism
  • Mice
  • Mice, Mutant Strains
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Protein Biosynthesis / physiology*
  • Protein Multimerization / physiology*
  • Reactive Oxygen Species / metabolism


  • Cst3 protein, mouse
  • Cystatin C
  • Reactive Oxygen Species