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Molecular Mechanisms of Cleavage and Secretion of Glycosyltransferases
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Many glycosyltransferases are type II membrane proteins and are retained in the Golgi apparatus, or endoplasmic reticulum, for glycoconjugate biosynthesis. Some of these enzymes are cleaved at their “stem region” by an endogenous protease, or proteases, and secreted out of the cell [1]. Indeed, many glycosyltransferases have been found as extracellular sercreted forms in body fluids such as serum and milk. It has been well documented that the proteolytic cleavage and secretion of glycosyltransferases are affected by various pathological conditions such as malignant transformation and inflammation, but the molecular mechanisms underlying the cleavage and secretion have not yet been clarified.
Identification of an endogenous protease for the cleavage would be an important initial step for a better understanding of the molecular mechanisms. Alzheimer's  -secretase has been recently identified as a protease that cleaves a glycosyltransferase,  2,6-sialyltransferase [2]. -secretase was originally defined to be a protease that cleaved amyloid precursor protein to produce -amyloid [3]. Deposition of -amyloid in the brain is an initiation step of Alzheimer’s disease. Thus -secretase is a crucial protease in the pathogenesis of the disease. -secretase cleaves amyloid precursor protein in the trans-Golgi network. It would be reasonable that -secretase also cleaves 2,6-sialyltransferase that is localized in the same subcellular component. However, each glycosyltransferase in the trans-Golgi network has an independent rate for the cleavage and secretion. It remains to be clarified, therefore, whether the cleavage rates depend on susceptibility or accessibility of glycosyltransferases to -secretase. Alternatively, endogenous proteases other than -secretase may be involved in the glycosyltransferase cleavage.
It would be important to clarify what kinds of proteases are additionally involved and how they are regulated for their cleavage of glycosyltransferases, which are localized in subcellular compartments such as Golgi apparatus and endoplasmic reticulum. These proteases including -secretase may not be merely degradation machinery for excess glycosyltransferases but important one for controlling the glycoconjugate expression. This issue should be addressed in the future. |
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Yasuhiro Hashimoto and Shinobu Kitazume
(Glyco-Chain Functions Laboratory, RIKEN Frontier Research System) |
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| References |
(1) |
Paulson JC, Colley KJ, J. Biol. Chem. 264, 17615-17618, 1989 |
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(2) |
Kitazume S, et al., Proc. Natl. Acad. Sci. USA 98, 13554-13559, 2001 |
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(3) |
Selkoe DJ, Physiol. Rev. 81, 741-766, 2001 |
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| Jun. 15, 2002 |
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