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

Elena Friedmann; Ehud Hauben; Kerstin Maylandt; Simone Schleeger; Sarah Vreugde; Stefan F. Lichtenthaler; Peer Hendrik Kuhn; Daniela Stauffer; Giorgio Rovelli; Bruno Martoglio

doi:10.1038/ncb1440

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

Elena Friedmann, Ehud Hauben, Kerstin Maylandt, Simone Schleeger, Sarah Vreugde, Stefan F. Lichtenthaler, Peer Hendrik Kuhn, Daniela Stauffer, Giorgio Rovelli, Bruno Martoglio

Research output: Contribution to journal › Article › peer-review

177 Scopus citations

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.

Original language	English
Pages (from-to)	843-848
Number of pages	6
Journal	Nature Cell Biology
Volume	8
Issue number	8
DOIs	https://doi.org/10.1038/ncb1440
State	Published - Aug 2006
Externally published	Yes

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title = "SPPL2a and SPPL2b promote intramembrane proteolysis of TNFα 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 (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.",

author = "Elena Friedmann and Ehud Hauben and Kerstin Maylandt and Simone Schleeger and Sarah Vreugde and Lichtenthaler, {Stefan F.} and Kuhn, {Peer Hendrik} and Daniela Stauffer and Giorgio Rovelli and Bruno Martoglio",

note = "Funding Information: 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.",

year = "2006",

month = aug,

doi = "10.1038/ncb1440",

language = "English",

volume = "8",

pages = "843--848",

journal = "Nature Cell Biology",

issn = "1465-7392",

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number = "8",

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T1 - SPPL2a and SPPL2b promote intramembrane proteolysis of TNFα in activated dendritic cells to trigger IL-12 production

AU - Friedmann, Elena

AU - Hauben, Ehud

AU - Maylandt, Kerstin

AU - Schleeger, Simone

AU - Vreugde, Sarah

AU - Lichtenthaler, Stefan F.

AU - Kuhn, Peer Hendrik

AU - Stauffer, Daniela

AU - Rovelli, Giorgio

AU - Martoglio, Bruno

N1 - Funding Information: 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.

PY - 2006/8

Y1 - 2006/8

N2 - 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.

AB - 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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EP - 848

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 8

ER -

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

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