A novel mannose-binding lectin/ficolin-associated protein is highly expressed in heart and skeletal muscle tissues and inhibits complement activation.
The human lectin complement pathway involves circulating complexes consisting of mannose-binding lectin (MBL) or three ficolins (ficolin-1, -2, and -3) in association with three MBL/ficolin-associated serine proteases (MASP) (MASP-1, -2, and -3) and a nonenzymatic sMAP. MASP-1 and MASP-3 (MASP1 isoforms 1 and 2, respectively) are splice variants of the MASP1 gene, whereas MASP-2 and sMAP are splice variants of the MASP2 gene. We have identified a novel serum protein of 45 kDa that is associated with MBL and the ficolins. This protein is named MBL/ficolin-associated protein 1 (MAP-1 corresponding to MASP1 isoform 3). The transcript generating MAP-1 (MASP1_v3) contains exons 1-8 and a novel exon encoding an in-frame stop codon. The corresponding protein lacks the serine protease domains but contains most of the common heavy chain of MASP-1 and MASP-3. Additionally MAP-1 contains 17 unique C-terminal amino acids. By use of quantitative PCR and MAP-1-specific immunohistochemistry, we found that MAP-1 is highly expressed in myocardial and skeletal muscle tissues as well as in liver hepatocytes with a different expression profile than that observed for MASP-1 and MASP-3. MAP-1 co-precipitated from human serum with MBL, ficolin-2, and ficolin-3, and recombinant MAP-1 was able to inhibit complement C4 deposition via both the ficolin-3 and MBL pathway. In conclusion we have identified a novel 45-kDa serum protein derived from the MASP1 gene, which is highly expressed in striated muscle tissues. It is found in complex with MBL and ficolins and may function as a potent inhibitor of the complement system in vivo.
Skjoedt
Mikkel-Ole
MO
Laboratory of Molecular Medicine, Department of Clinical Immunology, Rigshospitalet, Faculty of Health Sciences, University Hospital of Copenhagen, DK 2100 Copenhagen, Denmark.
Hummelshoj
Tina
T
Palarasah
Yaseelan
Y
Honore
Christian
C
Koch
Claus
C
Skjodt
Karsten
K
Garred
Peter
P
D017398:Alternative Splicing / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D000918:Antibody Specificity; D016466:CHO Cells; D003167:Complement Activation / Q000502:physiology*; D006224:Cricetinae; D003412:Cricetulus; D003429:Cross Reactions; D006801:Humans; D007150:Immunohistochemistry; D007536:Isomerism; D037102:Lectins / Q000378:metabolism*; D037241:Mannose-Binding Lectins / Q000378:metabolism*; D050606:Mannose-Binding Protein-Associated Serine Proteases / Q000737:chemistry / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008969:Molecular Sequence Data; D008970:Molecular Weight; D018482:Muscle, Skeletal / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000097604:Ficolins
D037102:Lectins; D037241:Mannose-Binding Lectins; D050606:Mannose-Binding Protein-Associated Serine Proteases; D012333:RNA, Messenger; D000097604:Ficolins; C084067:MASP1 protein, human; C105296:MASP2 protein, human