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J. Biol. Chem., Vol. 282, Issue 3, 1851-1862, January 19, 2007

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Cathepsin E Deficiency Induces a Novel Form of Lysosomal Storage Disorder Showing the Accumulation of Lysosomal Membrane Sialoglycoproteins and the Elevation of Lysosomal pH in Macrophages^*

Michiyo Yanagawa¹, Takayuki Tsukuba¹, Tsuyoshi Nishioku, Yoshiko Okamoto^¶, Kuniaki Okamoto^||, Ryosuke Takii, Yoshihiro Terada, Keiichi I. Nakayama^**, Tomoko Kadowaki, and Kenji Yamamoto²

From the Departments of Pharmacology and Fixed Prosthodontics, Graduate School of Dental Science, Kyushu University, Fukuoka 812-8582, the ^¶Department of Biochemistry, Daiichi University College of Pharmaceutical Sciences, Fukuoka 815-8511, the ^||Department of Dental Pharmacology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8588, and the ^**Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan

Cathepsin E, an endolysosomal aspartic proteinase predominantly expressed in cells of the immune system, has an important role in immune responses. However, little is known about the precise roles of cathepsin E in this system. Here we report that cathepsin E deficiency (CatE^-/-) leads to a novel form of lysosome storage disorder in macrophages, exhibiting the accumulation of the two major lysosomal membrane sialoglycoproteins LAMP-1 and LAMP-2 and the elevation of lysosomal pH. These striking features were also found in wild-type macrophages treated with pepstatin A and Ascaris inhibitor. Whereas there were no obvious differences in their expression, biosynthesis, and trafficking between wild-type and CatE^-/- macrophages, the degradation rates of these two membrane proteins were apparently decreased as a result of cathepsin E deficiency. Because there was no difference in the vacuolar-type H⁺-ATPase activity in both cell types, the elevated lysosomal pH in CatE^-/- macrophages is most likely due to the accumulation of these lysosomal membrane glycoproteins highly modified with acidic monosaccharides, thereby leading to the disruption of non-proton factors controlling lysosomal pH. Furthermore, the selective degradation of LAMP-1 and LAMP-2, as well as LIMP-2, was also observed by treatment of the lysosomal membrane fraction isolated from wild-type macrophages with purified cathepsin E at pH 5. Our results thus suggest that cathepsin E is important for preventing the accumulation of these lysosomal membrane sialoglycoproteins that can induce a new form of lysosomal storage disorder.

Received for publication, May 1, 2006 , and in revised form, November 7, 2006.

^* 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.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Graduate School of Dental Science, Kyushu University, Fukuoka 812-8582, Japan. Tel.: 81-92-642-6337; Fax: 81-92-642-6342; E-mail: kyama{at}dent.kyushu-u.ac.jp.

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