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PRELP Protein Inhibits the Formation of the Complement Membrane Attack Complex

Happonen, Kaisa LU ; Melin Fürst, Camilla LU ; Saxne, Tore LU ; Heinegård, Dick LU and Blom, Anna LU (2012) In Journal of Biological Chemistry 287(11). p.8092-8100
Abstract
PRELP is a 58-kDa proteoglycan found in a variety of extracellular matrices, including cartilage and at several basement membranes. In rheumatoid arthritis (RA), the cartilage tissue is destroyed and fragmented molecules, including PRELP, are released into the synovial fluid where they may interact with components of the complement system. In a previous study, PRELP was found to interact with the complement inhibitor C4b-binding protein, which was suggested to locally down-regulate complement activation in joints during RA. Here we show that PRELP directly inhibits all pathways of complement by binding C9 and thereby prevents the formation of the membrane attack complex (MAC). PRELP does not interfere with the interaction between C9 and... (More)
PRELP is a 58-kDa proteoglycan found in a variety of extracellular matrices, including cartilage and at several basement membranes. In rheumatoid arthritis (RA), the cartilage tissue is destroyed and fragmented molecules, including PRELP, are released into the synovial fluid where they may interact with components of the complement system. In a previous study, PRELP was found to interact with the complement inhibitor C4b-binding protein, which was suggested to locally down-regulate complement activation in joints during RA. Here we show that PRELP directly inhibits all pathways of complement by binding C9 and thereby prevents the formation of the membrane attack complex (MAC). PRELP does not interfere with the interaction between C9 and already formed C5b-8, but inhibits C9 polymerization thereby preventing formation of the lytic pore. The alternative pathway is moreover inhibited already at the level of C3-convertase formation due to an interaction between PRELP and C3. This suggests that PRELP may down-regulate complement attack at basement membranes and on damaged cartilage and therefore limit pathological complement activation in inflammatory disease such as RA. The net outcome of PRELP-mediated complement inhibition will highly depend on the local concentration of other complement modulating molecules as well as on the local concentration of available complement proteins. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
287
issue
11
pages
8092 - 8100
publisher
ASBMB
external identifiers
  • wos:000301349400025
  • pmid:22267731
  • scopus:84858009778
ISSN
1083-351X
DOI
10.1074/jbc.M111.291476
language
English
LU publication?
yes
id
233026bc-6853-472f-8868-476e25a34392 (old id 2515553)
date added to LUP
2012-05-07 08:34:01
date last changed
2017-03-26 03:08:22
@article{233026bc-6853-472f-8868-476e25a34392,
  abstract     = {PRELP is a 58-kDa proteoglycan found in a variety of extracellular matrices, including cartilage and at several basement membranes. In rheumatoid arthritis (RA), the cartilage tissue is destroyed and fragmented molecules, including PRELP, are released into the synovial fluid where they may interact with components of the complement system. In a previous study, PRELP was found to interact with the complement inhibitor C4b-binding protein, which was suggested to locally down-regulate complement activation in joints during RA. Here we show that PRELP directly inhibits all pathways of complement by binding C9 and thereby prevents the formation of the membrane attack complex (MAC). PRELP does not interfere with the interaction between C9 and already formed C5b-8, but inhibits C9 polymerization thereby preventing formation of the lytic pore. The alternative pathway is moreover inhibited already at the level of C3-convertase formation due to an interaction between PRELP and C3. This suggests that PRELP may down-regulate complement attack at basement membranes and on damaged cartilage and therefore limit pathological complement activation in inflammatory disease such as RA. The net outcome of PRELP-mediated complement inhibition will highly depend on the local concentration of other complement modulating molecules as well as on the local concentration of available complement proteins.},
  author       = {Happonen, Kaisa and Melin Fürst, Camilla and Saxne, Tore and Heinegård, Dick and Blom, Anna},
  issn         = {1083-351X},
  language     = {eng},
  number       = {11},
  pages        = {8092--8100},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {PRELP Protein Inhibits the Formation of the Complement Membrane Attack Complex},
  url          = {http://dx.doi.org/10.1074/jbc.M111.291476},
  volume       = {287},
  year         = {2012},
}