Signal peptide peptidases and gamma-secretase: Cousins of the same protease family?

Signal peptide peptidase (SPIP) is an unusual aspartyl protease,
which mediates clearance of signal peptides by proteolysis within
the endoplasmic reticulum (ER). Like presenilins, which provide the
proteolytically active subunit of the,gamma-secretase complex, SPP
contains a conserved GxGD motif in its C-terminal domain which is
critical for its activity. While SPIP is known to be an aspartyl
protease of the GxGD type, several presenilin homologues/SPP-like
proteins (PSHs/ SPPL) of unknown function have been identified by
database searches. In contrast to SPP and SPPL3, which are both
restricted to the endoplasmic reticulum, SPPL2b is targeted through
the secretory pathway to endosomes/lysosomes. As suggested by the
differential subcellular localization of SPPL2b and SPPL3 distinct
phenotypes were found upon antisense gripNA-mediated knockdown in
zebrafish. spp and sppl3 knockdowns in zebrafish result in cell
death within the central nervous system, whereas reduction of
sppl2b expression causes erythrocyte accumulation in an enlarged
caudal vein. Moreover, expression of D/A mutants of the putative
C-terminal active sites of spp, sppl2, and spp13 produced
phenocopies of the respective knockdown phenotypes. These data
suggest that all investigated PSHs/SPPLs are members of the novel
family of GxGD aspartyl proteases. More recently, it was shown that
SPPL2b utilizes multiple intramembrane cleavages to liberate the
TNF(x intracellular domain into the cytosol and to release the
C-terminal counterpart into the lumen. These findings suggest
common principles of intramembrane proteolysis by GxGD type
aspartyl proteases. In this article,we will review the similarities
of SPPs and gamma-secretase based on recent findings by us and
others.