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Presenilin Roles in Intracellular Trafficking
Evidence for the involvement of presenilins in intracellular trafficking comes from the
study of the highly conserved C. elegans presenilin homolog, SEL-12, which was
originally isolated as a suppressor of a gain-of-function mutation in lin-12 (7).
LIN-12 is a C. elegans homolog of Notch. The lin-12 gene is involved in
the signaling pathway that is responsible for vulval development in C. elegans.
Gain-of-function mutations in lin-12 result in a “multivulva” or MUV
phenotype. Recessive mutations in the gene sel-12 suppress the MUV phenotype
associated with the gain-of-function lin-12 mutation (Figure 1c). One hypothesis
for the mechanism of SEL-12 suppression, is that loss-of-function mutations in sel-12 might
disrupt the localization and recycling of LIN-12. This hypothesis is supported by studies
in C. elegans that indicate sel-12 mutations are unable to suppress the
constitutively active phenotype of truncated LIN-12 [LIN-12 containing only the
intracellular domain (ref. 23)]. Although another explanation of the same result is that
SEL-12 is required for the processing of the activated LIN-12 receptor (24 see: Presenilin
Roles in APP processing).
Further evidence comes from the diverged presenilin family member, SPE-4 from C.
elegans, which is involved in the delivery of cytoplasmic components into the
spermatid during development. Mutations in spe-4 disrupt the structure and of an
ER/Golgi derived organelle that is responsible for packaging and delivering cellular
components to the spermatid (6). Additionally, cells of spe-4 mutant animals fail
to correctly segregate tubulin during spermatogenesis, and instead tubulin accumulates in
the arrested cells in an unusual membrane associated location after meiosis is completed
(18).
A third line of evidence for the intracellular trafficking role comes from analysis of
proteins that interact with the human presenilins. Using yeast two-hybrid screens,
researchers identified QM/Jun interacting factor (Jif-1) as a protein that associates with
PS1 (13). QM/Jif-1 is a negative regulator of c-Jun. Not only are QM/Jif-1 and PS1 shown
to interact by a variety of assays (pulldown assays, immunoprecipitation), but PS1 appears
to be involved in the translocation of and colocalizes with QM/Jif-1 to the nucleus. These
results are consistent with the suggestion that the presenilins act as proteins that are
responsible for intracellular transport and localization of certain cytoplasmic
components.
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