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J. Biol. Chem., Vol. 282, Issue 38, 28285-28295, September 21, 2007

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HtrA2 Regulates -Amyloid Precursor Protein (APP) Metabolism through Endoplasmic Reticulum-associated Degradation^*

Henri J. Huttunen¹, Suzanne Y. Guénette¹, Camilla Peach, Christopher Greco, Weiming Xia^¶, Doo Yeon Kim, Cory Barren, Rudolph E. Tanzi, and Dora M. Kovacs²

From the Neurobiology of Disease Laboratory and the Genetics and Aging Research Unit, Massachusetts General Institute for Neurodegenerative Disease (MIND), Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129 and the ^¶Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115

Alzheimer disease-associated -amyloid peptide is generated from its precursor protein APP. By using the yeast two-hybrid assay, here we identified HtrA2/Omi, a stress-responsive chaperone-protease as a protein binding to the N-terminal cysteinerich region of APP. HtrA2 coimmunoprecipitates exclusively with immature APP from cell lysates as well as mouse brain extracts and degrades APP in vitro. A subpopulation of HtrA2 localizes to the cytosolic side of the endoplasmic reticulum (ER) membrane where it contributes to ER-associated degradation of APP together with the proteasome. Inhibition of the proteasome results in accumulation of retrotranslocated forms of APP and increased association of APP with HtrA2 and Derlin-1 in microsomal membranes. In cells lacking HtrA2, APP holoprotein is stabilized and accumulates in the early secretory pathway correlating with elevated levels of APP C-terminal fragments and increased A secretion. Inhibition of ER-associated degradation (either HtrA2 or proteasome) promotes binding of APP to the COPII protein Sec23 suggesting enhanced trafficking of APP out of the ER. Based on these results we suggest a novel function for HtrA2 as a regulator of APP metabolism through ER-associated degradation.

Received for publication, April 6, 2007 , and in revised form, July 31, 2007.

^* This work was supported in part by grants from the NINDS, National Institutes of Health (to D. M. K.) and the Helsingin Sanomat Centennial Foundation and Maud Kuistila Memorial Foundation (to H. J. H.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S3.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Neurobiology of Disease Laboratory, Massachusetts General Hospital, Harvard Medical School, 114 16th St., Charlestown, MA 02129. Tel.: 617-726-3668; Fax: 617-724-1823; E-mail: Dora_Kovacs{at}hms.harvard.edu.

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