ICAM-1 isoforms: specific activity and sensitivity to cleavage by leukocyte elastase and cathepsin G.
The extracellular moiety of ICAM-1 consists of five Ig-like domains, the first and third domains mediating adhesion to integrin ligands. The ICAM-1 gene, however, gives rise to the expression of five alternative splice variants containing two, three, or four Ig-like domains. In this work, we have investigated whether the rearrangement of the architecture of ICAM-1 affects its structural properties and function. We showed that, in contrast to the common form, all alternative isoforms of ICAM-1 were susceptible to cleavage by leukocyte elastase and cathepsin G. We found that the length of an isoform did not influence the susceptibility to proteolysis. The molecular diversity provided by the skipping of entire Ig domains and the level of expression on the APC, however, significantly influenced their ability to potentiate the proliferation of T cells. Finally, we found that the expression of minor ICAM-1 isoforms encoding the third Ig-like domains was sufficient to sustain neutrophil infiltration in the liver and confer exon-5-targeted ICAM-1-deficient mice susceptibility to LPS-induced septic shock. These findings not only demonstrate that ICAM-1 isoforms are fully functional, but support the concept that alternative RNA splicing in the Ig superfamily may fulfill distinct roles during the development of the immune response.
INRS-Institut Armand-Frappier, Université du Québec, Laval, Canada.
Olivier
O
Robledo
Anne
A
Papaioannou
Benoit
B
Ochietti
Claire
C
Beauchemin
Doris
D
Legault
André
A
Cantin
Philip D
PD
King
Claude
C
Daniel
Valery Yu
VY
Alakhov
Edouard F
EF
Potworowski
Yves
Y
St-Pierre
D017398:Alternative Splicing; D000818:Animals; D017951:Antigen Presentation; D056649:Cathepsin G; D002403:Cathepsins / Q000502:physiology*; D002460:Cell Line; D003550:Cystic Fibrosis / Q000201:enzymology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology*; D019272:Leukocyte Elastase / Q000502:physiology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020033:Protein Isoforms; D012697:Serine Endopeptidases; D013183:Sputum / Q000201:enzymology
D016169:Lymphocyte Function-Associated Antigen-1; D016177:Macrophage-1 Antigen; D020033:Protein Isoforms; D018799:Intercellular Adhesion Molecule-1; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; C534096:Ctsg protein, mouse; D019272:Leukocyte Elastase