Presenilins are components of the gamma-secretase protein complex that mediates intramembranous cleavage of PAPP and Notch proteins. A C. elegans genetic screen revealed two genes,
aph-1 and
pen-2, encoding multipass transmembrane proteins, that interact strongly with
sel-12/presenilin and
aph-2/nicastrin. Human
aph-1 and
pen-2 partially rescue the C. elegans mutant phenotypes, demonstrating conserved functions. The human genes must be provided together to rescue the mutant phenotypes, and the inclusion of presenilin-1 improves rescue, suggesting that they interact closely with each other and with presenilin. RNAi-mediated inactivation of
aph-1,
pen-2, or nicastrin in cultured Drosophila cells reduces gamma-secretase cleavage of PAPP and Notch substrates and reduces the levels of processed presenilin.
aph-1 and
pen-2, like nicastrin, are required for the activity and accumulation of gamma-secretase.