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

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 (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.

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

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amino Acid Sequence / genetics
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Amyloid Precursor Protein Secretases / genetics*
  • Aspartic Acid Endopeptidases / antagonists & inhibitors
  • Aspartic Acid Endopeptidases / genetics
  • Humans
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / genetics*
  • Peptides / antagonists & inhibitors
  • Peptides / genetics*
  • Peptides / metabolism
  • Proteolysis*
  • Substrate Specificity


  • Membrane Proteins
  • Peptides
  • dermcidin
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • SPPL2a protein, human
  • SPPL2b protein, human