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
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 |
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المؤلفون: | Kiriakidis, S, Hoer, SS, Burrows, N, Biddlecome, G, Khan, MN, Thinnes, CC, Schofield, CJ, Rogers, N, Botto, M, Paleolog, E, Maxwell, PH |
المساهمون: | Hoer, Simon [0000-0002-6071-967X], Burrows, Natalie [0000-0001-6591-5971], Maxwell, Patrick [0000-0002-0338-2679], Apollo - University of Cambridge Repository |
المصدر: | Kidney International |
بيانات النشر: | Elsevier, 2017. |
سنة النشر: | 2017 |
مصطلحات موضوعية: | EXPRESSION, Male, complement C1q, education, Procollagen-Proline Dioxygenase, chemical and pharmacologic phenomena, Hydroxylation, Cell Line, Hypoxia-Inducible Factor-Proline Dioxygenases, Mice, HIF, Animals, Humans, BIOSYNTHESIS, Complement Pathway, Classical, REPERFUSION INJURY, Hypoxia, hypoxia-inducible factor, health care economics and organizations, prolyl hydroxylase inhibitors, Science & Technology, Macrophages, 4-HYDROXYLASE, 1103 Clinical Sciences, Anemia, Prolyl-Hydroxylase Inhibitors, Urology & Nephrology, 1ST COMPONENT, Mice, Inbred C57BL, Basic Research, MYOCARDIAL-INFARCTION, CELLS, SUBCOMPONENT, Female, Kidney Diseases, Life Sciences & Biomedicine, Protein Processing, Post-Translational |
الوصف: | 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. |
وصف الملف: | application/pdf |
URL الوصول: | https://explore.openaire.eu/search/publication?articleId=pmid_dedup__::aafa03069cf585cf50fbe586cffc9787 https://ora.ox.ac.uk/objects/uuid:04b6cb9c-ef1b-4569-b5b4-0aaba4762379 |
حقوق: | OPEN |
رقم الأكسشن: | edsair.pmid.dedup....aafa03069cf585cf50fbe586cffc9787 |
قاعدة البيانات: | OpenAIRE |
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