SPPL2a and SPPL2b promote intramembrane proteolysis of TNFalpha in activated dendritic cells to trigger IL-12 production.
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.
Friedmann
Elena
E
Institute of Biochemistry, Swiss Federal Institute of Technology (ETH), ETH Hoenggerberg, 8092 Zurich, Switzerland.
Hauben
Ehud
E
Maylandt
Kerstin
K
Schleeger
Simone
S
Vreugde
Sarah
S
Lichtenthaler
Stefan F
SF
Kuhn
Peer-Hendrik
PH
Stauffer
Daniela
D
Rovelli
Giorgio
G
Martoglio
Bruno
B
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*
D001426:Bacterial Proteins; D007527:Isoenzymes; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D016282:Aspartic Acid Endopeptidases; C095652:signal peptidase II