Presenilin modulates Pen-2 levels posttranslationally by protecting it from proteasomal degradation.
The gamma-secretase complex functions to cleave several type I transmembrane proteins within their transmembrane domains. These include the amyloid precursor protein, which is central to Alzheimer's disease pathogenesis, as well as N-cadherin and Notch, which regulate transcription. This complex is composed of four requisite integral membrane proteins: presenilin 1 (PS1) or presenilin 2 (PS2), nicastrin, Pen-2, and Aph-1. How these proteins coordinately regulate one another and assemble to form a functional complex is not well understood. In this report we demonstrate that PS1 selectively enhances the stability of Pen-2 protein but not that of nicastrin or Aph-1. In the absence of PS1, Pen-2 was rapidly degraded by the proteasome. As PS1 levels increased, so too did the half-life of Pen-2 and therefore its steady-state levels. In addition, Pen-2 protein levels correlated with PS1 levels not only in cell culture but in transgenic mouse models as well. The genetic absence of PS1 and PS2, and therefore of gamma-secretase-dependent mediation of transcriptional activity, did not affect Pen-2 mRNA levels. Rather, presenilin (PS) regulates Pen-2 levels posttranslationally by preventing its degradation by the proteasome. Thus, the amount of Pen-2 protein is effectively titrated by its PS binding partner, and the rapidity with which Pen-2 is degraded in the absence of PS interactions could provide a mechanism to tightly regulate gamma-secretase complex assembly.
Crystal
Adam S
AS
Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Morais
Vanessa A
VA
Fortna
Ryan R
RR
Carlin
Dan
D
Pierson
Theodore C
TC
Wilson
Christina A
CA
Lee
Virginia M-Y
VM
Doms
Robert W
RW
D000544:Alzheimer Disease / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053764:Presenilin-1; D053766:Presenilin-2; D046988:Proteasome Endopeptidase Complex; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D021381:Protein Transport; D011784:Quail; D014158:Transcription, Genetic
D008565:Membrane Proteins; D009097:Multienzyme Complexes; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; C469349:PSENEN protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse; D046988:Proteasome Endopeptidase Complex