title: Innate immune recognition triggers secretion of lysosomal enzymes by macrophages.
abstract: Gamma interferon-induced lysosomal thiolreductase (GILT) is expressed constitutively in antigen-presenting cells, where it reduces disulfide bonds to facilitate antigen presentation. GILT is synthesized as an enzymatically active precursor protein and is processed in early endosomes to yield the mature enzyme. The exposure of the promonocytic cell line THP-1 to Escherichia coli causes a differentiation-dependent induction of GILT expression in which the majority of precursor GILT is secreted as active enzyme. We confirm this result in cultured primary monocytes and macrophages, and demonstrate, as an in vivo correlate of the phenomenon, upregulation of precursor GILT levels in the serum of mice injected with lipopolysaccharide. We show that macrophage differentiation is accompanied by a transcriptional downregulation of mannose-6-phosphorylation, which likely prevents the recognition and proper sorting of soluble lysosomal enzymes by the mannose-6-phosphate receptors. We provide evidence for a mechanism of generalized soluble lysosomal enzyme secretion through the constitutive secretory pathway.
authors.affiliation: Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, 300 Cedar Street, New Haven, CT, USA.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Lackman
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Jamieson
authors.forename: Janice M
authors.initials: JM
authors.lastname: Griffith
authors.forename: Hans
authors.initials: H
authors.lastname: Geuze
authors.forename: Peter
authors.initials: P
authors.lastname: Cresswell
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002403:Cathepsins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D002460:Cell Line; D015870:Gene Expression; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D016253:Microscopy, Immunoelectron; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000097:blood / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases / Q000235:genetics; D010766:Phosphorylation; D021381:Protein Transport / Q000187:drug effects; D017527:Receptor, IGF Type 2 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D049231:Saposins / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000502:physiology; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics
chemical_list: C497811:LAMP2 protein, human; D008070:Lipopolysaccharides; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins; C483345:PSAP protein, human; D017527:Receptor, IGF Type 2; D049231:Saposins; D051197:Toll-Like Receptor 4; D050862:Oxidoreductases Acting on Sulfur Group Donors; D017855:Transferases (Other Substituted Phosphate Groups); C511050:GNPTAB protein, human; C504791:GNPTG protein, human; D010727:Phosphoric Diester Hydrolases; C026645:N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase; D002403:Cathepsins; C028217:cathepsin S