title: Inhibition of glutaminyl cyclase attenuates cell migration modulated by monocyte chemoattractant proteins.
abstract: QC (glutaminyl cyclase) catalyses the formation of N-terminal pGlu (pyroglutamate) in peptides and proteins. pGlu formation in chemoattractants may participate in the regulation of macrophage activation and migration. However, a clear molecular mechanism for the regulation is lacking. The present study examines the role of QC-mediated pGlu formation on MCPs (monocyte chemoattractant proteins) in inflammation. We demonstrated in vitro the pGlu formation on MCPs by QC using MS. A potent QC inhibitor, PBD150, significantly reduced the N-terminal uncyclized-MCP-stimulated monocyte migration, whereas pGlu-containing MCP-induced cell migration was unaffected. QC small interfering RNA revealed a similar inhibitory effect. Lastly, we demonstrated that inhibiting QC can attenuate cell migration by lipopolysaccharide. These results strongly suggest that QC-catalysed N-terminal pGlu formation of MCPs is required for monocyte migration and provide new insights into the role of QC in the inflammation process. Our results also suggest that QC could be a drug target for some inflammatory disorders.
authors: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
authors: Yi-Ling
authors: YL
authors: Chen
authors: Kai-Fa
authors: KF
authors: Huang
authors: Wen-Chih
authors: WC
authors: Kuo
authors: Yan-Chung
authors: YC
authors: Lo
authors: Yu-May
authors: YM
authors: Lee
authors: Andrew H-J
authors: AH
authors: Wang
mesh_terms: D019881:Aminoacyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D001483:Base Sequence; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008958:Models, Molecular; D018945:Monocyte Chemoattractant Proteins / Q000737:chemistry / Q000502:physiology*; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D054730:Protein Interaction Domains and Motifs; D034741:RNA, Small Interfering / Q000235:genetics; D020298:U937 Cells
chemical_list: D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D018945:Monocyte Chemoattractant Proteins; D034741:RNA, Small Interfering; D019881:Aminoacyltransferases; C059280:glutaminyl-peptide cyclotransferase