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.

Helical stability of the GnTV transmembrane domain impacts on SPPL3 dependent cleavage.

Papadopoulou AA, Stelzer W, Silber M, Schlosser C, Spitz C, Haug-Kröper M, Straub T, Müller SA, Lichtenthaler SF, Muhle-Goll C, Langosch D, Fluhrer R.

Sci Rep. 2022 Dec 5;12(1):20987. doi: 10.1038/s41598-022-24772-8. PMID: 36470941

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

Signaling Functions of Intramembrane Aspartyl-Proteases.

Papadopoulou AA, Fluhrer R.

Front Cardiovasc Med. 2020 Dec 14;7:591787. doi: 10.3389/fcvm.2020.591787. eCollection 2020. PMID: 33381526 Free PMC article. Review.

Physiological functions of SPP/SPPL intramembrane proteases.

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

Cell Mol Life Sci. 2020 Aug;77(15):2959-2979. doi: 10.1007/s00018-020-03470-6. Epub 2020 Feb 12. PMID: 32052089 Free PMC article. Review.

Signal peptide peptidase-like 2c impairs vesicular transport and cleaves 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 May;20(5). pii: e48133. doi: 10.15252/embr.201948133. No abstract available.  PMID: 31061204 Free PMC Article

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

CLN5 is cleaved by members of the SPP/SPPL family to produce a mature soluble protein.

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

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