title: Cleavage of Signal Regulatory Protein α (SIRPα) Enhances Inflammatory Signaling.
abstract: Signal regulatory protein α (SIRPα) is a membrane glycoprotein immunoreceptor abundant in cells of monocyte lineage. SIRPα 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-κB signaling in macrophages. Here we observed that proteolysis of SIRPα 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 SIRPα fragment by γ-secretase was identified. Ectopic expression of a SIRPα mutant plasmid encoding a proteolytically resistant form in HeLa cells inhibited activation of the NF-κB pathway and suppressed STAT1 phosphorylation in response to TNFα to a greater extent than expression of wild-type SIRPα. Conversely, overexpression of plasmids encoding the proteolytically cleaved SIRPα fragments in cells resulted in enhanced STAT-1 and NF-κB pathway activation. Thus, the data suggest that combinatorial actions of ADAM10 and γ-secretase on SIRPα cleavage promote inflammatory signaling.
authors.affiliation: From the Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine and.
authors.forename: James D
authors.initials: JD
authors.lastname: Londino
authors.affiliation: From the Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine and.
authors.forename: Dexter
authors.initials: D
authors.lastname: Gulick
authors.affiliation: From the Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine and Vascular Medicine Institute, Starzl Transplantation Institute, Department of Pharmacology and Chemical Biology, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Isenberg
authors.affiliation: From the Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine and Medical Specialty Service Line, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania 15213, Department of Cell Biology and Physiology and Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, mallampallirk@upmc.edu.
authors.forename: Rama K
authors.initials: RK
authors.lastname: Mallampalli
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000943:Antigens, Differentiation; D008565:Membrane Proteins; D016328:NF-kappa B; D011971:Receptors, Immunologic; C501920:SIRPA protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human
keywords: ADAM10; endotoxin; epithelium; inflammation; lung; protein degradation