Regulation of tyrosinase trafficking and processing by presenilins: partial loss of function by familial Alzheimer's disease mutation.
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.
Wang
Runsheng
R
Huffington Center on Aging and Departments of Molecular and Human Genetics and Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Tang
Phuong
P
Wang
Pei
P
Boissy
Raymond E
RE
Zheng
Hui
H
D000544:Alzheimer Disease / Q000196:embryology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism; D004848:Epithelium / Q000196:embryology / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D008543:Melanins / Q000096:biosynthesis; D008544:Melanocytes / Q000378:metabolism / Q000648:ultrastructure; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D014442:Monophenol Monooxygenase / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D010858:Pigmentation; D053764:Presenilin-1; D053766:Presenilin-2; D021381:Protein Transport; D012160:Retina / Q000196:embryology / Q000378:metabolism; D012867:Skin / Q000196:embryology / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D008543:Melanins; D008565:Membrane Proteins; D053764:Presenilin-1; D053766:Presenilin-2; D014443:Tyrosine; D014442:Monophenol Monooxygenase