Aph-1 is required to regulate Presenilin-mediated gamma-secretase activity and cell survival in Drosophila wing development.
Aph-1 is a multipass transmembrane protein and an essential component of the Presenilin (Psn)-mediated gamma-secretase complex. During protease assembly, Aph-1 stabilizes the newly synthesized Psn holoprotein to facilitate generation of the active form of Psn, which is a Psn-NTF/Psn-CTF heterodimer produced through a Presenilinase-initiated endoproteolytic cleavage of the Psn holoprotein. Although it is clear that loss of Aph-1 activity leads to failure of Psn heterodimer formation, little is understood about whether Aph-1 plays a role in regulating gamma-secretase activity in addition to assisting Psn maturation. Using various modified Psn forms that do not require endoproteolysis or have a large deletion of the cytosolic loop, we show that in Drosophila Aph-1 is still required for gamma-secretase activity independent of its role in promoting Psn endoproteolysis. In addition, our results indicate that Aph-1 is required to promote cell survival in the wing imaginal disc; aph-1 mutant cells are lost either through cell death or because of a defect in cell proliferation. This function of Aph-1 is independent of its role in regulating gamma-secretase activity, but possibly involves downregulating the activity of uncleaved Psn holoprotein.
Cooper
Emilie
E
Deng
Wu-Min
WM
Chung
Hui-Min
HM
D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016923:Cell Death / Q000235:genetics; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D019281:Dimerization; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D053763:Presenilins / Q000235:genetics / Q000378:metabolism*; D020836:Protein Structure, Quaternary / Q000502:physiology; D014921:Wings, Animal / Q000196:embryology*
C500358:Aph-1 protein, Drosophila; D029721:Drosophila Proteins; D008565:Membrane Proteins; D053763:Presenilins; D053829:Amyloid Precursor Protein Secretases