Complement C1q is hydroxylated by collagen prolyl 4 hydroxylase, and is sensitive to off target inhibition by prolyl hydroxylase domain inhibitors that stabilise Hypoxia Inducible Factor
التفاصيل البيبلوغرافية
العنوان:
Complement C1q is hydroxylated by collagen prolyl 4 hydroxylase, and is sensitive to off target inhibition by prolyl hydroxylase domain inhibitors that stabilise Hypoxia Inducible Factor
Hoer, Simon [0000-0002-6071-967X], Burrows, Natalie [0000-0001-6591-5971], Maxwell, Patrick [0000-0002-0338-2679], Apollo - University of Cambridge Repository
C1q is part of the C1 macromolecular complex that mediates the classical complement activation pathway, a major arm of innate immune defence. C1q is composed of A, B, and C chains that require post-translational prolyl-4-hydroxylation of their N-terminal collagen-like domain to enable formation of the functional triple helical multimers. The prolyl-4-hydroxylase(s) that hydroxylate C1q have not previously been identified. Recognised prolyl-4-hydroxylases include collagen prolyl- 4-hydroxylases (CP4H) and the more recently described prolyl hydroxylase domain (PHD) enzymes that act as oxygen sensors regulating hypoxia-inducible factor (HIF). We show that several small molecule prolyl-hydroxylase inhibitors that activate HIF also potently suppress C1q secretion by human macrophages. However, reducing oxygenation to a level that activates HIF does not compromise C1q hydroxylation. In vitro studies showed that a C1q A chain peptide is not a substrate for PHD2, but is a substrate for CP4H1. Circulating levels of C1q did not differ between wild type mice and mice with genetic deficits in PHD enzymes, but were reduced by administration of the prolyl-hydroxylase inhibitors. Our findings imply that C1q is hydroxylated by CP4H, but not the structurally related PHD hydroxylases. A reduction in C1q levels may be an important side-effect of small molecule PHD inhibitors developed as treatments for renal anemia, as an “off-target” consequence of inhibiting CP4H.
