Proteomic identification of sorting nexin 6 as a negative regulator of BACE1-mediated APP processing

Abstract

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 (A beta), 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 (sAPP beta) and cell-associated fragments (C99), resulting in increased A beta 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 A beta biogenesis. Our study identifies a novel cellular pathway by which SNX6 negatively modulates BACE1-mediated cleavage of APP.-Okada, H., Zhang, W., Peterhoff, C., Hwang, J. C., Nixon, R. A., Ryu, S. H., Kim, T.-W. Proteomic identification of sorting nexin 6 as a negative regulator of BACE1-mediated APP processing. FASEB J. 24, 2783-2794 (2010). www.fasebj.org