O-GlcNAc and Its Function
|Many nuclear and cytoplasmic proteins are glycosylated on
serine or threonine residue with a monosaccharide, -acetylglucosamine,
in an O-glycosidic linkage which is termed O-GlcNAc (Fig.
1). O-GlcNAc is present in all eukaryotes. O-GlcNAc modification
(O-GlcNAcylation) is one of the post-translational modifications and involved
in signal transduction (1). O-GlcNAc and O-phosphate alternatively occupy
the same or adjacent site. For example, the C-terminal domain of RNA polymerase
II, Thr58 of c-myc, which is a "hot spot" in mutation
for lymphomas, and Ser16 of estrogen receptor are modified
not only by O-GlcNAc but also a phosphate group. The half life of O-GlcNAc
is shorter than that of the polypeptides. O-GlcNAc modification is changed
dynamically by certain stimuli such as TPA, okadaic acid and others. Therefore,
it is suggested that one of the functions of O-GlcNAc is regulation of
transient phosphorylation. The glycosylation sites with O-GlcNAc have
no obvious consensus sequences. Unlike phosphorylation, O-GlcNAcylation
has not been observed in tyrosine residues.
|Immunohistochemical analysis of the localization of O-GlcNAc
in rat pancreas revealed that O-GlcNAc is expressed on proteins in the
nucleus and cytoplasm of endocrine cells in the islets of Langerhans (2).
To date, a large number of cytoplasmic and nuclear proteins such as transcription
factors, nuclear pore proteins, oncogene products, tumor suppressors and
cytoskeletal proteins have been shown to be modified by O-GlcNAc. They
have two common features: (1) they are also phosphorylated and (2) they
form multimeric complexes with other proteins reversibly. Thus, the O-GlcNAcylation
might be a regulatory modification analogous to phosphorylation, involved
in signal transduction and protein multimerization.
Enzymes for addition and for removal of the O-GlcNAc residue have been purified and cloned (3, 4). UDP-GlcNAc: polypeptide O-acetylglucosaminyltransferase (O-GlcNAc transferase) adds acetylglucosamine to the hydroxyl group of serine or threonine residue(s) of proteins. The O-GlcNAc transferase is itself modified by O-GlcNAc and the phosphate group, and has 11 tetratricopeptide repeats (TPR) which are involved in protein-protein interaction. Recently, using a yeast two-hybrid system we identified GABAA receptor-associated protein (GRIF-1) and its novel homolog, OIP106 as O-GlcNAc transferase interacting proteins(5). O-GlcNAc transferase is abundant in brain and pancreas. Disruption of O-GlcNAc transferase activity leads to the death of mouse embryonic stem cells. This suggests that the O-GlcNAc modification is essential in cells. O-GlcNAc specific acetylglucosaminidase (O-GlcNAcase) removes O-GlcNAc residues from proteins. O-GlcNAcase is a cytosolic neutral -acetylglucosaminidase, unlike the acidic lysosomal hexosaminidases. The regulation of O-GlcNAcylation by these two enzymes is analogous to that of phosphorylation by kinases and phosphatases (Fig. 2).
There is a growing body of evidence that the aberrant O-GlcNAc modification is correlated with diabetes, tumorigenesis, Alzheimer's disease (1, 6-9). More detailed studies are necessary for determining the functions of O-GlcNAc in a variety of biological systems.
(Department of Anatomy, Kyorin University School of Medicine)
|Jan. 22, 2003|