Reference : Complement C1q is hydroxylated by collagen prolyl 4 hydroxylase and is sensitive to o...
Scientific journals : Article
Physical, chemical, mathematical & earth Sciences : Chemistry
http://hdl.handle.net/10993/39147
Complement C1q is hydroxylated by collagen prolyl 4 hydroxylase and is sensitive to off-target inhibition by prolyl hydroxylase domain inhibitors that stabilize hypoxia-inducible factor.
English
Kiriakidis, Serafim [> >]
Hoer, Simon S. [> >]
Burrows, Natalie [> >]
Biddlecome, Gloria [> >]
Khan, Moddasar N. [> >]
Thinnes, Cyrille mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) >]
Schofield, Christopher J. [> >]
Rogers, Norma [> >]
Botto, Marina [> >]
Paleolog, Ewa [> >]
Maxwell, Patrick H. [> >]
2017
Kidney international
92
4
900-908
Yes (verified by ORBilu)
0085-2538
1523-1755
United States
[en] Anemia/drug therapy/etiology ; Animals ; Cell Line ; Complement C1q/analysis/metabolism ; Complement Pathway, Classical ; Female ; Humans ; Hydroxylation ; Hypoxia/metabolism ; Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism ; Kidney Diseases/blood/drug therapy/pathology ; Macrophages/drug effects/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Procollagen-Proline Dioxygenase/antagonists & inhibitors/metabolism ; Prolyl-Hydroxylase Inhibitors/pharmacology/therapeutic use ; Protein Processing, Post-Translational ; complement C1q ; hypoxia-inducible factor ; prolyl hydroxylase inhibitors
[en] Complement C1q is part of the C1 macromolecular complex that mediates the classical complement activation pathway: a major arm of innate immune defense. 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 the formation of the functional triple helical multimers. The prolyl 4-hydroxylase(s) that hydroxylate C1q have not previously been identified. Recognized 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 or mice with genetic deficits in PHD enzymes, but were reduced by prolyl hydroxylase inhibitors. Thus, C1q is hydroxylated by CP4H, but not the structurally related PHD hydroxylases. Hence, reduction of C1q levels may be an important off-target side effect of small molecule PHD inhibitors developed as treatments for renal anemia.
http://hdl.handle.net/10993/39147
Copyright (c) 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

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