| First Author | Londino JD | Year | 2015 |
| Journal | J Biol Chem | Volume | 290 |
| Issue | 52 | Pages | 31113-25 |
| PubMed ID | 26534964 | Mgi Jnum | J:227412 |
| Mgi Id | MGI:5700440 | Doi | 10.1074/jbc.M115.682914 |
| Citation | Londino JD, et al. (2015) Cleavage of Signal Regulatory Protein alpha (SIRPalpha) Enhances Inflammatory Signaling. J Biol Chem 290(52):31113-25 |
| abstractText | Signal regulatory protein alpha (SIRPalpha) is a membrane glycoprotein immunoreceptor abundant in cells of monocyte lineage. SIRPalpha ligation by a broadly expressed transmembrane protein, CD47, results in phosphorylation of the cytoplasmic immunoreceptor tyrosine-based inhibitory motifs, resulting in the inhibition of NF-kappaB signaling in macrophages. Here we observed that proteolysis of SIRPalpha during inflammation is regulated by a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), resulting in the generation of a membrane-associated cleavage fragment in both THP-1 monocytes and human lung epithelia. We mapped a charge-dependent putative cleavage site near the membrane-proximal domain necessary for ADAM10-mediated cleavage. In addition, a secondary proteolytic cleavage within the membrane-associated SIRPalpha fragment by gamma-secretase was identified. Ectopic expression of a SIRPalpha mutant plasmid encoding a proteolytically resistant form in HeLa cells inhibited activation of the NF-kappaB pathway and suppressed STAT1 phosphorylation in response to TNFalpha to a greater extent than expression of wild-type SIRPalpha. Conversely, overexpression of plasmids encoding the proteolytically cleaved SIRPalpha fragments in cells resulted in enhanced STAT-1 and NF-kappaB pathway activation. Thus, the data suggest that combinatorial actions of ADAM10 and gamma-secretase on SIRPalpha cleavage promote inflammatory signaling. |
