期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 103, 期 2, 页码 353-358出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0509822102
关键词
gamma-secretase; pigmentation; melanocyte; knock-out; knock-in
资金
- NIAMS NIH HHS [R01 AR045429, AR45429] Funding Source: Medline
- NIA NIH HHS [T32 AG000183, R01 AG020670, AG20670] Funding Source: Medline
- NINDS NIH HHS [NS40039, R01 NS040039] Funding Source: Medline
Presenilins (PS) are required for gamma-secretase cleavage of multiple type I membrane proteins including the amyloid precursor protein and Notch and also have been implicated in regulating intracellular protein trafficking and turnover. Using genetic and pharmacological approaches, we reveal here a unique function of PS in the pigmentation of retinal pigment epithelium and epidermal melanocytes. PS deficiency leads to aberrant accumulation of tyrosinase (Tyr)-containing 50-nm post-Golgi vesicles that are normally destined to melanosomes. This trafficking is gamma-secretase-dependent, and abnormal localization of Tyr in the absence of PS is accompanied by the simultaneous accumulation of its C-terminal fragment. Furthermore, we show that the PS1M146V familial Alzheimer's disease mutation exhibits a partial loss-of-function in pigment synthesis. Our results identify Tyr and related proteins as physiological substrates of PS and link gamma-secretase activity with intracellular protein transport.
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