Signal-peptide-peptidase-like 2a (SPPL2a) is targeted to lysosomes/late endosomes by a tyrosine motif in its C-terminal tail

Signal-peptide-peptidase-like 2A (SPPL2a), an aspartyl intramembrane protease, has been implicated in the proteolysis of TNF-alpha, Fas Ligand and Bri2. Here, we show that endogenous SPPL2a – in agreement with overexpression studies – is localised in membranes of lysosomes/late endosomes. Furthermore, we have analysed the molecular determinants for lysosomal sorting of SPPL2a by creating chimaeric constructs between SPPL2a and its plasma membrane localised homologue SPPL2b. Lysosomal transport of SPPL2a critically depends on its cytosolic carboxyterminal tail. A canonical tyrosine-based sorting motif of the YXXø type at position 498 is sufficient to direct SPPL2a to lysosomal/late endosomal compartments. This motif accounts for the differential localisation of the homologous proteases SPPL2a and SPPL2b and thereby influences the access to substrates and biological function of SPPL2a.Structured summary of protein interactionsLAMP2 and SPPL2a colocalize by fluorescence microscopy (view interaction)

► Endogenous signal-peptide-peptidase-like 2A (SPPL2a), an intramembrane protease, is localised in lysosomes/late endosomes.
► Lysosomal transport of SPPL2a critically depends on its cytosolic carboxyterminal tail.
► The C-terminal tail of SPPL2a is able to direct the plasma-membrane localised homologue SPPL2b to lysosomes/late endosomes.
► A canonical tyrosine-based sorting motif of the YXXø type is sufficient for lysosomal/late endosomal targeting of SPPL2a.