Pen-2 is sequestered in the endoplasmic reticulum and subjected to ubiquitylation and proteasome-mediated degradation in the absence of presenilin
Anna Bergman, Emil Hansson, Sharon E. Pursglove, Mark R. Farmery, Lars Lannfelt, Urban Lendahl, Johan Lundkvist, Jan Näslund
Bok Engelsk 2004
| Utgitt | 2004
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| Omfang | 30 s. + vedl.
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| Opplysninger | ABSTRACT:The y-secretase complex catalyzes intramembrane proteolysis of a number of transmembrane proteins, including amyloid precursor protein, Notch, ErbB4 and Ecadherin. y-Secretase is known to contain four major protein constituents: presenilin(PS), nicastrin, Aph-l,and Pen-2, all of which are integral membrane proteins. There is increasing evidence that the formation of the complex and the stability of individual components are tightly controlled in the cell, assuring correct composition of functional complexes. In this report, we investigate the topology, localization and the mechanism for destabilization of Pen-2 in relation to PS function. We show that PSl regulates the subcellular localization of Pen-2: in the absence of PS, Pen-2 is sequestered in the endoplasmic reticulum (ER) and not transported to post-ER compartments, where the mature y-secretase complexes reside. PS-deficiency also leads to destabilization of Pen-2, which is alleviated by proteasome inhibitors. In keeping with this, we show that Pen-2, which adopts a hairpin structure with the N and C termini facing the luminal space, is ubiquitylated prior to degradation and presurnably retrotranslocated from the ER to the cytoplasm. Collectively, our datasugge st that failure to become incorporated into the y-secretase complex leads to degradation of Pen-2 through the ER-associated degradation (ERAD)-proteasome pathway.
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