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Biochim Biophys Acta Mol Cell Res. 2017 Nov;1864(11 Pt B):2169-2182. doi: 10.1016/j.bbamcr.2017.06.007. Epub 2017 Jun 15.

Signal peptide peptidase and SPP-like proteases - Possible therapeutic targets?

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Biochemical Institute, Christian Albrechts University of Kiel, Otto-Hahn-Platz 9, D-24118 Kiel, Germany.
Biomedizinisches Centrum (BMC), Ludwig Maximilians University of Munich, Feodor-Lynen-Strasse 17, D-81377 Munich, Germany; DZNE - German Center for Neurodegenerative Diseases, Munich, Feodor-Lynen-Strasse 17, D-81377 Munich, Germany.
Biochemical Institute, Christian Albrechts University of Kiel, Otto-Hahn-Platz 9, D-24118 Kiel, Germany. Electronic address:


Signal peptide peptidase (SPP) and the four homologous SPP-like proteases SPPL2a, SPPL2b, SPPL2c and SPPL3 are GxGD-type intramembrane-cleaving proteases (I-CLIPs). In addition to divergent subcellular localisations, distinct differences in the mechanistic properties and substrate requirements of individual family members have been unravelled. SPP/SPPL proteases employ a catalytic mechanism related to that of the γ-secretase complex. Nevertheless, differential targeting of SPP/SPPL proteases and γ-secretase by inhibitors has been demonstrated. Furthermore, also within the SPP/SPPL family significant differences in the sensitivity to currently available inhibitory compounds have been reported. Though far from complete, our knowledge on pathophysiological functions of SPP/SPPL proteases, in particular based on studies in mice, has been significantly increased over the last years. Based on this, inhibition of distinct SPP/SPPL proteases has been proposed as a novel therapeutic concept e.g. for the treatment of autoimmunity and viral or protozoal infections, as we will discuss in this review. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John.


Autoimmunity; ERAD; Intramembrane proteolysis; SPPL proteases; Signal peptide peptidase; γ-Secretase

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