Annexin 1 cleavage in activated neutrophils: a pivotal role for proteinase 3.
Annexin 1 is an anti-inflammatory protein that plays a key role in innate immunity by modulating the activation of several types of cells, including neutrophils. Here we have developed a cleavage assay using tagged annexin 1 and observed marked activity in the membrane fraction of activated neutrophils. A combination of inhibitors, transfected cells, and proteomic analyses allowed us to identify proteinase 3 as the main enzyme responsible for this cleavage in the N terminus region of the protein, at least in the context of neutrophil activation. Because annexin 1 is an important endogenous anti-inflammatory mediator, blocking its cleavage by proteinase 3 would augment its homeostatic pro-resolving actions and could represent an opportunity for innovative anti-inflammatory drug discovery.
Vong
Linda
L
William Harvey Research Institute, Barts and The London, Charterhouse Square, London EC1M 6BQ, United Kingdom.
D'Acquisto
Fulvio
F
Pederzoli-Ribeil
Magali
M
Lavagno
Luisa
L
Flower
Roderick J
RJ
Witko-Sarsat
Véronique
V
Perretti
Mauro
M
D000595:Amino Acid Sequence; D017305:Annexin A1 / Q000737:chemistry* / Q000378:metabolism; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D004847:Epithelial Cells / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D018922:HL-60 Cells; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D053146:Myeloblastin / Q000378:metabolism*; D018375:Neutrophil Activation; D009504:Neutrophils / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid
D017305:Annexin A1; D000893:Anti-Inflammatory Agents; D053146:Myeloblastin