Prof. Regina Fluhrer

Universität Augsburg


Project P2: Substrate Portfolio of the Signal Peptide Peptidase-like 2 (SPPL2) family


Signal peptide peptidase (SPP) and the homologous SPP-like (SPPL) proteases, SPPL2a, SPPL2b, SPPL2c and SPPL3, belong to the family of GxGD proteases and thus represent one prototype of intramembrane cleaving enzymes.


In the first funding period we applied a proteome wide screen and identified a variety of new candidate substrates for SPPL2a, SPPL2b and, in addition, also for SPPL2c, a so far orphan protease. Moreover, we identified three new SPPL2a/b substrates by candidate approach and determined the C-terminal SPPL2 cleavage sites in these substrates.


We will now validate the newly identified candidate substrates and determine the precise determinants within these substrates that affect recognition by SPPL2 and processivity. Finally we will investigate the specific prerequisites for substrate recognition within the SPPL2 proteases.

Publications (FOR 2290)

Non-canonical Shedding of TNFα by SPPL2a Is Determined by the Conformational Flexibility of Its Transmembrane Helix.

Spitz C, Schlosser C, Guschtschin-Schmidt N, Stelzer W, Menig S, Götz A, Haug-Kröper M, Scharnagl C, Langosch D, Muhle-Goll C, Fluhrer R.

iScience. 2020 Nov 5;23(12):101775. doi: 10.1016/j.isci.2020.101775. eCollection 2020 Dec 18.PMID: 33294784


Physiological functions of SPP/SPPL intramembrane proteases.

Mentrup T, Cabrera-Cabrera F, Fluhrer R, Schröder B.

Cell Mol Life Sci. 2020 Feb 12. doi: 10.1007/s00018-020-03470-6. [Epub ahead of print] Review. PMID: 32052089


Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis.

Mentrup T, Theodorou K, Cabrera-Cabrera F, Helbig AO, Happ K, Gijbels M, Gradtke AC, Rabe B, Fukumori A, Steiner H, Tholey A, Fluhrer R, Donners M, Schröder B.

J Exp Med. 2019 Apr 1;216(4):807-830. doi: 10.1084/jem.20171438. Epub 2019 Feb 28. PMID: 30819724


Signal Peptide Peptidase-Like 2c (SPPL2c) impairs vesicular transport and cleavage of SNARE proteins.

Papadopoulou AA, Müller SA, Mentrup T, Shmueli MD, Niemeyer J, Haug-Kröper M, von Blume J, Mayerhofer A, Feederle R, Schröder B, Lichtenthaler SF, Fluhrer R.

EMBO Rep. 2019 Feb 7. pii: e46451. doi: 10.15252/embr.201846451. [Epub ahead of print] PMID: 30733281


The intramembrane protease SPPL2c promotes male germ cell development by cleaving phospholamban.

Niemeyer J, Mentrup T, Heidasch R, Müller SA, Biswas U, Meyer R, Papadopoulou AA, Dederer V, Haug-Kröper M, Adamski V, Lüllmann-Rauch R, Bergmann M, Mayerhofer A, Saftig P, Wennemuth G, Jessberger R, Fluhrer R, Lichtenthaler SF, Lemberg MK, Schröder B.

EMBO Rep. 2019 Feb 7. pii: e46449. doi: 10.15252/embr.201846449. [Epub ahead of print]


Proteolytic ectodomain shedding of membrane proteins in mammals-hardware, concepts, and recent developments.

Lichtenthaler SF, Lemberg MK, Fluhrer R.

EMBO J. 2018 Aug 1;37(15). pii: e99456. doi: 10.15252/embj.201899456. Epub 2018 Jul 5. Review.


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

Mentrup T, Loock AC, Fluhrer R, Schröder B.

Biochim Biophys Acta. 2017 Nov;1864(11 Pt B):2169-2182.


An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function.

Schlepckow K, Kleinberger G, Fukumori A, Feederle R, Lichtenthaler SF, Steiner H, Haass C.

EMBO Mol Med. 2017 Oct;9(10):1356-1365.


Latest emerging functions of SPP/SPPL intramembrane proteases.

Mentrup T, Fluhrer R, Schröder B.

Eur J Cell Biol. 2017 Aug;96(5):372-382. doi: 10.1016/j.ejcb.2017.03.002. Epub 2017 Mar 16. Review. PMID: 28366434


Jules F, Sauvageau E, Dumaresq-Doiron K, Mazzaferri J, Haug-Kröper M, Fluhrer R, Costantino S, Lefrancois S.

Exp Cell Res. 2017 Aug 1;357(1):40-50. doi: 10.1016/j.yexcr.2017.04.024. Epub 2017 Apr 22. PMID: 28442266




FOR 2290 PI's

Research Unit FOR 2290