title: Latest emerging functions of SPP/SPPL intramembrane proteases.
abstract: Signal peptide peptidase (SPP) and the four related SPP-like (SPPL) proteases are homologues of the presenilins, which comprise the catalytic centre of the γ-secretase complex. SPP/SPPL proteases are GxGD-type aspartyl intramembrane proteases selective for substrates with a type II membrane topology. Subcellular localisations of SPP/SPPL proteases range from the early secretory pathway to the plasma membrane and the endocytic system. Similarly diverse are their functional roles at the cellular level covering the turnover of signal peptides and membrane proteins, a contribution to the ERAD pathway as well as the regulation of cellular protein glycosylation and certain signaling pathways. Much less well understood are the physiological functions of SPP/SPPL proteases in complex organisms. Whereas a major role of SPPL2a for homeostasis of B cells and dendritic cells has been documented in mice, in vivo functions of SPP and the other SPPLs remain largely elusive to date. SPP/SPPL proteases contribute to regulated intramembrane proteolysis (RIP), a sequential processing of single-spanning transmembrane proteins by an ectodomain sheddase and an intramembrane-cleaving protease (I-CLIP). However, recent studies reported the cleavage of tail-anchored and multi-pass membrane proteins by SPP as well as the capability of SPPL3 to accept substrates without a preceding ectodomain shedding. This revealed that the mechanistic properties within this family are more diverse than initially thought. With this review, we aim to provide an update on recent achievements in defining the function and (patho-) physiological relevance of SPP/SPPL proteases and to highlight open questions in the field.
authors.affiliation: Biochemical Institute, Christian Albrechts University of Kiel, Otto-Hahn-Platz 9, D-24118 Kiel, Germany.
authors.forename: Torben
authors.initials: T
authors.lastname: Mentrup
authors.affiliation: Biomedizinisches Centrum (BMC), Ludwig Maximilians University of Munich, Feodor-Lynen-Strasse 17, D-81377 Munich, Germany; DZNE-German Center for Neurodegenerative Diseases, Feodor-Lynen-Strasse 17, D-81377 Munich, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Fluhrer
authors.affiliation: Biochemical Institute, Christian Albrechts University of Kiel, Otto-Hahn-Platz 9, D-24118 Kiel, Germany. Electronic address: baschroeder@biochem.uni-kiel.de.
authors.forename: Bernd
authors.initials: B
authors.lastname: Schröder
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases; D006801:Humans; D008565:Membrane Proteins
chemical_list: D008565:Membrane Proteins; D016282:Aspartic Acid Endopeptidases; C460085:signal peptide peptidase
keywords: ERAD; Ectodomain shedding; Intramembrane proteolysis; Proteostasis; SPPL proteases; Signal peptide peptidase