International Protease Network

Institute of Biochemistry
Swiss Federal Institute of Technology (ETH)
ETH-Hoenggerberg, 8093, Zurich, Switzerland
Email: bruno.martoglio@bc.biol.ethz.ch
Tel: +41-1-632 6347
Fax: +41-1-632-1269
Homepage:

Research

The main topic of our research is intramembrane proteolysis. We have identified the intramembrane cleaving aspartic protease SPP (for signal peptide peptidase). SPP cleaves a variety of signal peptides after they have been liberated from the precursor protein, and promotes the release of signal peptide fragments into the cytosol. Such peptides may have signalling or regulatory functions in the cell. In addition to the identification of the SPP, we have defined features substrates require for cleavage by SPP. Furthermore, we have identified one critical function of SPP in immune surveillance in humans (HLA-E epitope generation), and discovered that hepatitis C virus exploits SPP for processing of the viral polyprotein.
SPP is the prototypic member of a new family of intramembrane-cleaving aspartic proteases. They are related to the presenilins, which are considered to be catalytic subunits of g-secretase complexes implicated in the cause of Alzheimer?s disease. SPP and presenilins contain identical active site motifs. Not surprisingly, these proteases share overlapping inhibitor activities. Using SPP as a model protease, we are addressing the enzymology of the aspartic intramembrane-cleaving proteases. We are also aiming elucidating cellular functions of SPP and its homologous candidate proteases of which there are four present in the human genome. We expect these enzymes to promote activation of membrane-tethered factors as it appears typically for intramembrane-cleaving proteases.

Collaborations

Publications

Weihofen, A. and Martoglio, B. "Intramembrane-cleaving proteases; controlled liberation of functional proteins and peptides from membranes", Trends Cell Biol. 2003 13, 71-78.

Weihofen, A., Binns K., Lemberg, M.K., Ashman, K. and Martoglio, B. "Identification of signal peptide peptidase, a presenilin-type aspartic protease", Science 2002 296, 2215-2218.

Lemberg, M.K. and Martoglio, B. "Requirements for signal peptide peptidase-catalysed intramembrane proteolysis", Mol. Cell 2002 10, 735-744.

McLauchlan, J., Lemberg, M.K., Hope, R.G. and Martoglio, B. "Intramembrane proteolysis promotes trafficking of hepatitis C virus core protein to lipid droplets", EMBO J. 2002 21, 3980-3988.

Lemberg, M.K., Bland, F., Weihofen, A., Braud, V and Martoglio, B. "Intramembrane proteolysis of signal peptides: an essential step in the generation of HLA-E epitopes", J. Immunol. 2001 167, 6441-6446.