title: SPPL2a and SPPL2b promote intramembrane proteolysis of TNFalpha in activated dendritic cells to trigger IL-12 production.
abstract: Homologues of signal peptide peptidase (SPPLs) are putative aspartic proteases that may catalyse regulated intramembrane proteolysis of type II membrane-anchored signalling factors. Here, we show that four human SPPLs are each sorted to a different compartment of the secretory pathway. We demonstrate that SPPL2a and SPPL2b, which are sorted to endosomes and the plasma membrane, respectively, are functional proteases that catalyse intramembrane cleavage of tumour necrosis factor alpha (TNFalpha). The two proteases promoted the release of the TNFalpha intracellular domain, which in turn triggers expression of the pro-inflammatory cytokine interleukin-12 by activated human dendritic cells. Our study reveals a critical function for SPPL2a and SPPL2b in the regulation of innate and adaptive immunity.
authors.affiliation: Institute of Biochemistry, Swiss Federal Institute of Technology (ETH), ETH Hoenggerberg, 8092 Zurich, Switzerland.
authors.forename: Elena
authors.initials: E
authors.lastname: Friedmann
authors.forename: Ehud
authors.initials: E
authors.lastname: Hauben
authors.forename: Kerstin
authors.initials: K
authors.lastname: Maylandt
authors.forename: Simone
authors.initials: S
authors.lastname: Schleeger
authors.forename: Sarah
authors.initials: S
authors.lastname: Vreugde
authors.forename: Stefan F
authors.initials: SF
authors.lastname: Lichtenthaler
authors.forename: Peer-Hendrik
authors.initials: PH
authors.lastname: Kuhn
authors.forename: Daniela
authors.initials: D
authors.lastname: Stauffer
authors.forename: Giorgio
authors.initials: G
authors.lastname: Rovelli
authors.forename: Bruno
authors.initials: B
authors.lastname: Martoglio
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D018664:Interleukin-12 / Q000096:biosynthesis*; D007425:Intracellular Membranes / Q000187:drug effects* / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D034622:RNA Interference; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D007527:Isoenzymes; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D016282:Aspartic Acid Endopeptidases; C095652:signal peptidase II