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J. Biol. Chem., Vol. 277, Issue 33, 29737-29744, August 16, 2002
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From N-Acetylglucosamine-1-phosphodiester
Human Mannose 6-Phosphate-uncovering Enzyme Is Synthesized as a
Proenzyme That Is Activated by the Endoprotease Furin*
§,,, and
Novazyme Pharmaceuticals, Incorporated,
Oklahoma City, Oklahoma 73104 and the ¶ Department of Internal
Medicine, Washington University School of Medicine, St. Louis, Missouri
63110
-N-acetylglucosaminidase, also known as "uncovering"
enzyme (UCE), is localized in the trans-Golgi network,
where it removes a covering N-acetylglucosamine from the
mannose 6-phosphate recognition marker on lysosomal acid hydrolases.
Here we show that UCE is synthesized as an inactive proenzyme that is
activated by the endoprotease furin, which cleaves an RARLPR
D
sequence to release a 24-amino acid propiece. As furin is localized in
the trans-Golgi network, newly synthesized UCE is inactive
until it reaches this terminal Golgi compartment. LoVo cells (derived
from a human colon adenocarcinoma) lack furin activity and have
extremely low UCE activity. Addition of furin to LoVo cell extracts
restores UCE activity to normal levels, demonstrating that the UCE
proenzyme is stable in this cell type. LoVo cells secrete acid
hydrolases with phosphomannose diesters as a consequence of the
deficient UCE activity. This demonstrates for the first time that UCE
is the only enzyme in these cells capable of efficiently uncovering
phosphomannose diesters. UCE also hydrolyzes UDP-GlcNAc, a sugar donor
for Golgi N-acetylglucosaminyltransferases. The fact that
UCE is not activated until it reaches the trans-Golgi network may ensure that the pool of UDP-GlcNAc in the Golgi stack is
not depleted, thereby maintaining proper oligosaccharide assembly.
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Internal
Medicine, Div. of Hematology, Washington University School of Medicine,
660 S. Euclid Ave., Campus Box 8125, St. Louis, MO 63110. Tel.:
314-362-8803; Fax: 314-362-8826; E-mail: skornfel@im.wustl.edu.
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