Polyphosphate is a novel cofactor for regulation of complement by a serpin, C1 inhibitor

Blood. 2016 Sep 29;128(13):1766-76. doi: 10.1182/blood-2016-02-699561. Epub 2016 Jun 23.


The complement system plays a key role in innate immunity, inflammation, and coagulation. The system is delicately balanced by negative regulatory mechanisms that modulate the host response to pathogen invasion and injury. The serpin, C1-esterase inhibitor (C1-INH), is the only known plasma inhibitor of C1s, the initiating serine protease of the classical pathway of complement. Like other serpin-protease partners, C1-INH interaction with C1s is accelerated by polyanions such as heparin. Polyphosphate (polyP) is a naturally occurring polyanion with effects on coagulation and complement. We recently found that polyP binds to C1-INH, prompting us to consider whether polyP acts as a cofactor for C1-INH interactions with its target proteases. We show that polyP dampens C1s-mediated activation of the classical pathway in a polymer length- and concentration-dependent manner by accelerating C1-INH neutralization of C1s cleavage of C4 and C2. PolyP significantly increases the rate of interaction between C1s and C1-INH, to an extent comparable to heparin, with an exosite on the serine protease domain of the enzyme playing a major role in this interaction. In a serum-based cell culture system, polyP significantly suppressed C4d deposition on endothelial cells, generated via the classical and lectin pathways. Moreover, polyP and C1-INH colocalize in activated platelets, suggesting that their interactions are physiologically relevant. In summary, like heparin, polyP is a naturally occurring cofactor for the C1s:C1-INH interaction and thus an important regulator of complement activation. The findings may provide novel insights into mechanisms underlying inflammatory diseases and the development of new therapies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Blood Platelets / immunology
  • Blood Platelets / metabolism
  • Cells, Cultured
  • Complement C1 Inactivator Proteins / metabolism*
  • Complement C1 Inhibitor Protein
  • Complement C1s / chemistry
  • Complement C1s / metabolism
  • Complement C2 / metabolism
  • Complement C4 / metabolism
  • Complement Pathway, Classical
  • Complement System Proteins / metabolism*
  • Endothelial Cells / immunology
  • Endothelial Cells / metabolism
  • Heparin / metabolism
  • Humans
  • In Vitro Techniques
  • Polyphosphates / chemistry
  • Polyphosphates / metabolism*


  • Complement C1 Inactivator Proteins
  • Complement C1 Inhibitor Protein
  • Complement C2
  • Complement C4
  • Polyphosphates
  • SERPING1 protein, human
  • Heparin
  • Complement System Proteins
  • Complement C1s