title: PRELP protein inhibits the formation of the complement membrane attack complex.
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.
authors.affiliation: Department of Laboratory Medicine, Division of Medical Protein Chemistry, Wallenberg Laboratory, Skåne University Hospital, Lund University, S-20502 Lund, Sweden.
authors.forename: Kaisa E
authors.initials: KE
authors.lastname: Happonen
authors.forename: Camilla Melin
authors.initials: CM
authors.lastname: Fürst
authors.forename: Tore
authors.initials: T
authors.lastname: Saxne
authors.forename: Dick
authors.initials: D
authors.lastname: Heinegård
authors.forename: Anna M
authors.initials: AM
authors.lastname: Blom
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001485:Basement Membrane / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D003167:Complement Activation / Q000235:genetics; D050577:Complement C3-C5 Convertases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D050716:Complement C4b-Binding Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D003186:Complement C9 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015938:Complement Membrane Attack Complex / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003165:Complement System Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008297:Male
chemical_list: D050716:Complement C4b-Binding Protein; D003186:Complement C9; D015938:Complement Membrane Attack Complex; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C096382:PRELP protein, human; C042295:complement C5b-8 complex; D003165:Complement System Proteins; D050577:Complement C3-C5 Convertases