Journal of Biological Chemistry
Volume 280, Issue 12, 25 March 2005, Pages 11696-11703
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Enzyme Catalysis and Regulation
GGA Proteins Mediate the Recycling Pathway of Memapsin 2 (BACE)*

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Memapsin 2 (BACE, β-secretase) is a membrane-associated aspartic protease that initiates the hydrolysis of β-amyloid precursor protein (APP) leading to the production of amyloid-β (Aβ) and the progression of Alzheimer disease. Both memapsin 2 and APP are transported from the cell surface to endosomes where APP is cleaved by memapsin 2. We described previously that the cytosolic domain of memapsin 2 contains an acid cluster-dileucine motif (ACDL) that binds the VHS (Vps-27, Hrs, and STAM) domain of Golgi-localized γ-ear-containing ARF-binding (GGA) proteins (He, X., Zhu, G., Koelsch, G., Rodgers, K. K., Zhang, X. C., and Tang, J. (2003) Biochemistry 42, 12174–12180). Here we report that GGA proteins colocalize in the trans-Golgi network and endosomes with memapsin 2 and a memapsin 2 chimera containing a cytosolic domain of a mannose-6-phosphate receptor. Depleting cellular GGA proteins with RNA interference or mutation of serine 498 to stop the phosphorylation of ACDL resulted in the accumulation of memapsin 2 in early endosomes. A similar change of memapsin 2 localization also was observed when a retromer subunit, VPS26, was depleted. These observations suggest that GGA proteins function with the phosphorylated ACDL in the memapsin 2-recycling pathway from endosomes to trans-Golgi on the way back to the cell surface.

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Holder of J. G. Puterbaugh Chair in Medical Research at the Oklahoma Medical Research Foundation

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This work was supported in part by National Institutes of Health Grant AG-18933 and Alzheimer Association Pioneer Award (to J. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.