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SPPL2a and SPPL2b promote intramembrane proteolysis of TNFα in activated dendritic cells to trigger IL-12 production

Nature Cell Biology volume 8, pages 843–848 (2006)Cite this article

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 (TNFα). The two proteases promoted the release of the TNFα 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.

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Figure 1: SPP and SPPLs are sorted to distinct cellular compartments.
Figure 2: TNFα is processed by two proteolytic steps.
Figure 3: SPPL2a and SPPL2b are active aspartic proteases that act in RIP of TNFα.
Figure 4: TNFα-ICD triggers IL12 production in activated human dendritic cells in an SPPL2a- and SPPL2b-dependent manner.

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Acknowledgements

We thank B. Cenni and C. Haass for critical comments on the manuscript, and E. Duda and A. Helenius for antibodies. This work was supported by ETH Zurich and grants from the Centre of Neuroscience Zurich, and the National Competence Centre for Research on Neuronal Plasticity and Repair to B.M. E.H. was supported by a fellowship from the International Human Frontier Science Program Organization.

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Author notes

  1. Bruno Martoglio

    Present address: Expertise Platform Proteases, Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002, Basel, Switzerland

  2. Elena Friedmann and Ehud Hauben: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Biochemistry, Swiss Federal Institute of Technology (ETH), ETH Hoenggerberg, Zurich, 8092, Switzerland

    Elena Friedmann

  2. San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Via Olgettina 58, Milan, 20132, Italy

    Ehud Hauben

  3. Expertise Platform Proteases, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, 4002, Switzerland

    Kerstin Maylandt & Simone Schleeger

  4. Nervous Systems, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, 4002, Switzerland

    Daniela Stauffer & Giorgio Rovelli

  5. Molecular Histology and Cell Growth Unit, DIBIT, Via Olgettina 58, Milan, 20132, Italy

    Sarah Vreugde

  6. Adolf Butenandt-Institute, Ludwig-Maximilians-Universität, Munich, 80336, Germany

    Stefan F. Lichtenthaler & Peer-Hendrik Kuhn

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Contributions

E.F. and E.H. performed the main experimental work and data analysis with HeLa cells and dendritic cells, respectively, and contributed to the writing of the manuscript. K.M., S.S., S.V., S.F.L., P.H.K and D.S. also performed experimental work. R.G. contributed to project planning and writing of the manuscript. B.M. was responsible for project planning and guidance, data analysis and writing the manuscript.

Note: Supplementary Information is available on the Nature Cell Biology website.

Corresponding author

Correspondence to Bruno Martoglio.

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The authors declare no competing financial interests.

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Friedmann, E., Hauben, E., Maylandt, K. et al. SPPL2a and SPPL2b promote intramembrane proteolysis of TNFα in activated dendritic cells to trigger IL-12 production. Nat Cell Biol 8, 843–848 (2006). https://doi.org/10.1038/ncb1440

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