Letter abstract
Nature Cell Biology 8, 843 - 848 (2006)
Published online: 9 July 2006 | doi:10.1038/ncb1440
SPPL2a and SPPL2b promote intramembrane proteolysis of TNF
in activated dendritic cells to trigger IL-12 production
Elena Friedmann1,8, Ehud Hauben2,8, Kerstin Maylandt3, Simone Schleeger3, Sarah Vreugde5, Stefan F. Lichtenthaler6, Peer-Hendrik Kuhn6, Daniela Stauffer4, Giorgio Rovelli4 & Bruno Martoglio7
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 (TNF
). The two proteases promoted the release of the TNF 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.
- Institute of Biochemistry, Swiss Federal Institute of Technology (ETH), ETH Hoenggerberg, 8092 Zurich, Switzerland.
- San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Via Olgettina 58, 20132 Milan, Italy.
- Expertise Platform Proteases, Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002 Basel, Switzerland.
- Nervous Systems, Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002 Basel, Switzerland.
- Molecular Histology and Cell Growth Unit, DIBIT, Via Olgettina 58, 20132 Milan, Italy.
- Adolf Butenandt-Institute, Ludwig-Maximilians-Universität, 80336 Munich, Germany.
- Present address: Expertise Platform Proteases, Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002 Basel, Switzerland.
- These authors contributed equally to this work.
Correspondence to: Bruno Martoglio7 e-mail: bruno.martoglio@novartis.com
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