Proteomic identification of sorting nexin 6 as a negative regulator of BACE1-mediated APP processing.
The beta-site APP cleaving enzyme-1 (BACE1) mediates the first cleavage of the beta-amyloid precursor protein (APP) to yield the amyloid beta-peptide (Abeta), a key pathogenic agent in Alzheimer's disease (AD). Using a proteomic approach based on in-cell chemical cross-linking and tandem affinity purification (TAP), we herein identify sorting nexin 6 (SNX6) as a BACE1-associated protein. SNX6, a PX domain protein, is a putative component of retromer, a multiprotein cargo complex that mediates the retrograde trafficking of the cation-independent mannose-6-phosphate receptor (CI-MPR) and sortilin. RNA interference suppression of SNX6 increased BACE1-dependent secretion of soluble APP (sAPPbeta) and cell-associated fragments (C99), resulting in increased Abeta secretion. Furthermore, SNX6 reduction led to elevated steady-state BACE1 levels as well as increased retrograde transport of BACE1 in the endocytic pathway, suggesting that SNX6 modulates the retrograde trafficking and basal levels of BACE1, thereby regulating BACE1-mediated APP processing and Abeta biogenesis. Our study identifies a novel cellular pathway by which SNX6 negatively modulates BACE1-mediated cleavage of APP.
Okada
Hirokazu
H
Integrated Program in Cellular, Molecular, and Biophysical Studies, Columbia University Medical Center, New York, New York, USA.
Zhang
Wenzhu
W
Peterhoff
Corrinne
C
Hwang
Jeremy C
JC
Nixon
Ralph A
RA
Ryu
Sung H
SH
Kim
Tae-Wan
TW
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology; D002460:Cell Line; D006801:Humans; D006868:Hydrolysis; D021381:Protein Transport; D040901:Proteomics / Q000379:methods*; D012995:Solubility; D058305:Sorting Nexins; D033921:Vesicular Transport Proteins / Q000378:metabolism / Q000502:physiology*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; C431150:SNX6 protein, human; D058305:Sorting Nexins; D033921:Vesicular Transport Proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human