Imperial College London
Alternate

ProfessorMarinaBotto

Faculty of Medicine, Department of Immunology and Inflammation

Head of Department, Director of Bioservices
 
 
 
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Contact

 

+44 (0)20 3313 2316m.botto Website

 
 
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Assistant

 

Miss Claudia Rocchi +44 (0)20 3313 2315

 
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Location

 

9N10Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Kiriakidis:2017:10.1016/j.kint.2017.03.008,
author = {Kiriakidis, S and Hoer, SS and Burrows, N and Biddlecome, G and Khan, MN and Thinnes, CC and Schofield, CJ and Rogers, N and Botto, M and Paleolog, E and Maxwell, PH},
doi = {10.1016/j.kint.2017.03.008},
journal = {Kidney International},
pages = {900--908},
title = {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},
url = {http://dx.doi.org/10.1016/j.kint.2017.03.008},
volume = {92},
year = {2017}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Kiriakidis,S
AU  - Hoer,SS
AU  - Burrows,N
AU  - Biddlecome,G
AU  - Khan,MN
AU  - Thinnes,CC
AU  - Schofield,CJ
AU  - Rogers,N
AU  - Botto,M
AU  - Paleolog,E
AU  - Maxwell,PH
DO  - 10.1016/j.kint.2017.03.008
EP  - 908
PY  - 2017///
SN  - 0085-2538
SP  - 900
TI  - 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
T2  - Kidney International
UR  - http://dx.doi.org/10.1016/j.kint.2017.03.008
UR  - http://hdl.handle.net/10044/1/53177
VL  - 92
ER  -
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