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Nucleocytoplasmic shuttling of O-GlcNAcylated O-GlcNAc transferase
Hyeon Gyu Seo,Sang Yoon Park,Jin Won Cho 한국당과학회 2009 한국당과학회 학술대회 Vol.2009 No.1
It has been reported that one downstream effector produced from glucose is uridine diphosphate-N-acetly glucosamine (UDP-GlcNAc) via the hexoamine biosynthetic pathway (HBP). The dynamic cycle of addition and removal of O-linked-N-acetlyglucosamine (O-GlcNAc) to Ser/Thr residues is involved in regulating nuclear and cytoplasmic proteins. Nucleocytoplasmic O-linked GlcNAc transferases(ncOGT) which add a single GlcNAc to hydroxyl groups of serine and threonine residues. ncOGT is characterized by an amino terminuns bearing tetratricopeptide repeats (TPR), possible nuclear trafficking motifs, and a catalytic domain within its C-terminus. Interestingly, O-GlcNAc glycosylation occurs in nucelocytoplsmic O-linked GlcNAc transferase (ncOGT) as well and several sites have been identified mainly within TPR domain. We found O-GlcNAcylated site in ncOGT outside of TPR by using Q-TOF MS. Now we focus on the activities and function of ncOGT by mutagenesis studies. This ongoing effort would give us clear understanding of the key enzyme of O-GlcNAc metabolism and how the O-GlcNAc modification may be regulated.
Hyeon Gyu Seo,Han Byeol Kim,Min Jueng Kang,Ji Young Yoon,Tae Hyun Kweon,Yun Soo Park,Jingu Kang,Jinwoo Jung,Eugene C. Yi,Tae Ho Lee,Jin Won Cho 한국당과학회 2018 한국당과학회 학술대회 Vol.2018 No.07
X -linked inhibitor of apoptosis (XIAP), an inhibitor of apoptotic cell death, has a RING domain and functions as an E3 ligase, catalysing the ubiquitination of various substrates such as apoptosis-inducing factor, TGF- [3-activated kinase 1, and MEK kinase 2. Here, we identified 0-linked N-acetylglucosamine ( 0-GlcNAc) transferase ( OGT) as a substrate of XIAP. We showed that OGT catalyses the 0-GlcNAc modification of XIAP at serine 406, and this modification regulates the E3 ligase activity of XIAP towards OGT. Substitution of XIAP Ser406 by alanine decreased its E3 ligase activity toward OGT but not toward other substrates. Stable overexpression of XIAP in HCT116 human colorectal carcinoma cells decreased OGT protein levels and inhibited cancer cell growth and invasion. These results suggest that XIAP requires 0-GlcNAcylation in the regulation of its E3 ligase activity toward OGT, which leads to OGT degradation and the inhibition of cancer cell growth.
Role of Gangliosides in LMNA Mutation-induced Hutchinson-Gilford progeria syndrome model
Hyeon Gyu Lim,Seo Yi Lee,Won Seok Ju,Sung Youn Heo,Yu Na Seo,Young-Kug Choo,Dong Hoon Kwak 한국당과학회 2016 한국당과학회 학술대회 Vol.2016 No.07
Gangliosides has the important roles in interactions between cells and in signal transduction to regulate growth and differentiation. Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder wherein symptoms resembling aspects of aging are manifested at a very early age. Model of LMNA (Lamin A/C) mutation is known as a typical model for HPGS. However, roles of gangliosides in model of LMNA mutation (HGPS) is unclear. Therefore, this study investigated the expression patterns of gangliosides in model of LMNA-mutation. LMNA-mutation cells were primary cultured from spontaneous mouse LMNA-mutation model. Distribution of gangliosides in LMNA-mutation mouse was detected by HPTLC. We successes the primary cultured bone marrow-derived mesencymal stem cells from LMNA-mutation mouse. In addition, gangliosides in several tissues including liver, kidney and brain from LMNA-mutation mouse was various expressed compare with normal tissues. So, gangliosides may be related with LMNA in cell differentiation and proliferation. Therefore, this results suggested that gangliosides act important roles in aging and HGPS.
O-GlcNAc modification on O-GlcNAc transferase regulates its nuclear localization
Hyeon Gyu Seo,Joo Hwan Ryum,Han Byeol Kim,Jin Won Cho 한국당과학회 2013 한국당과학회 학술대회 Vol.2013 No.1
It has been reported that one of the downstream molecules generated from glucose is uridine diphosphate-N-acetly glucosamine(UDP-GlcNAc) via the hexoamine biopsynthetic pathway (HBP). The dynamic cycle of addition and removal of O-linked-N-acetlyglucosamine (O-GlcNAc) to Ser/Thr residues is involved in regulating nuclear and cytoplasmic proteins. Nucleocytoplasmic O-GlcNAc transferase (ncOGT) adds a single GlcNAc onto hydroxyl groups of serine and threonine residues. Interestingly, O-GlcNAc glycosylation occurs in ncOGT itself as well. O-GlcNAcylation on N-terminal domain of tetratricopeptide (TPR) repeats plays an important role in nuclear localization of ncOGT. Specific nuclear localization signals (NLS) in ncOGT has not been identified. We characterized the three amino acid motif as NLS because this motif is required for the nuclear import of non-diffusible β-galactosidase. Also, we show that ncOGT binds kayropherin α proteins, and the association between kayopherin α proteins and ncOGT is interfered by O-GlcNAcylation on TPR domain. Our finding suggests the mechanism how ncOGT can be localized in the nucleus and cytosol at the same time. Therefore our data may contribute to better understanding of the key enzyme of O-GlcNAc metabolism.
Hyeon Gyu Seo,Han Byeol Kim,Min Jueng Kang,Joo Hwan Rym,Eugene C. Yi,Jin Won Cho 한국당과학회 2016 한국당과학회 학술대회 Vol.2016 No.07
Nucleocytoplasmic O-GlcNAc transferase (OGT) attaches a single GlcNAc to hydroxyl groups of serine and threonine residues. Although the cellular localisation of OGT is important to regulate a variety of cellular processes, the molecular mechanisms regulating the nuclear localisation of OGT is unclear. Here, we characterised three amino acids (DFP; residues 451–453) as the nuclear localisation signal of OGT and demonstrated that this motif mediated the nuclear import of non-diffusible β-galactosidase. OGT bound the importin α5 protein, and this association was abolished when the DFP motif of OGT was mutated or deleted. We also revealed that O-GlcNAcylation of Ser389, which resides in the tetratricopeptide repeats, plays an important role in the nuclear localisation of OGT. Our findings may explain how OGT, which possesses a NLS, exists in the nucleus and cytosol simultaneously.
The mechanism and signal for the nuclear import of O-GlcNAc transferase
Hyeon Gyu Seo,Han Byeol Kim,Min Jueng Kang,Joo Hwan Rym,Eugene C. Yi,Jin Won Cho 한국당과학회 2016 한국당과학회 학술대회 Vol.2016 No.01
Uridine diphosphate-N-acetyl glucosamine, generated from glucose via the hexosamine biosynthetic pathway, is a substrate for O -linked-N-acetylglucosamine (O -GlcNAc). Addition and removal of O -linked-N-acetylglucosamine to Ser/Thr residues is a dynamic cycle and is involved in the regulation of nuclear and cytoplasmic proteins. Nucleocytoplasmic O -GlcNActransferase (OGT) attaches a single GlcNAc onto hydroxyl groups of serine and threonine residues. Although the cellular localization of OGT is important to regulate a variety of cellular processes, the molecular mechanism regulating the nuclear localization of OGT is unclear. Here, we characterized the NLS motif in OGT and this motif is required for the nuclear import of non-diffusible β -galactosidase. OGT bound the importin α5 protein, and this association was abolished when the NLS motif of ncOGT was mutated or deleted. We also revealed that O -GlcNAcylation on tetratricopeptide repeats (TPR) plays an important role in nuclear localization of OGT. Our finding suggests the mechanism behind how OGT can be localized in the nucleus and cytosol simultaneously.
Hyeon Gyu Seo,Han Byeol Kim,Tae Hyun kweon,Jingu Kang,SeongJin Son,Jinju Song,Won Ho Yang,Jin Won Cho 한국당과학회 2021 한국당과학회 학술대회 Vol.2021 No.01
XIAP (X-linked inhibitor of apoptosis) is an inhibitor of apoptotic cell death. It consists of a RING domain and functions as an E3 ligase. In this study, we identify OGT (O-linked N-acetylglucosamine (O-GlcNAc) Transferase) as a substrate of XIAP. In addition, we show that OGT catalyses the O-GlcNAcylation XIAP at serine 406, and that this modification in turn regulates the E3 ligase activity of XIAP towards OGT. Substitution of XIAP serine 406 by alanine decreased its E3 ligase activity toward OGT but not toward other substrates. Stable overexpression of XIAP in HCT116 human colorectal carcinoma cells decreased OGT protein levels and inhibited cancer cell growth and invasion. These results suggest that O-GlcNAcylation of XIAP is required for its E3 ligase activity toward OGT, which leads to OGT degradation and ultimately the inhibition of cancer cell growth.
The functional study of O-GlcNAcylated nucleocytoplasmic O-GlcNAc Transferase
Hyeon Gyu Seo,Sang Yoon Park,Jin Won Cho 한국당과학회 2008 한국당과학회 학술대회 Vol.2008 No.1
It has been reported that one downstream effector produced from glucose is uridine diphosphate-N-acetly glucosamine (UDP-GlcNAc) via the hexoamine biosynthetic pathway (HBP). The dynamic cycle of addition and removal of O-linked-N-acetlyglucosamine (O-GlcNAc) to Ser/Thr residues is involved in regulating nuclear and cytoplasmic proteins. Nucleocytoplasmic O-linked GlcNAc transferases(ncOGT) which add a single GlcNAc to hydroxyl groups of serine and threonine residues. ncOGT is characterized by an amino terminuns bearing tetratricopeptide repeats (TPR), possible nuclear trafficking motifs, and a catalytic domain within its C-terminus. Interestingly, O-GlcNAc glycosylation occurs in nucelocytoplsmic O-linked GlcNAc transferase (ncOGT) as well and several sites have been identified mainly within TPR domain. We found O-GlcNAcylated site in ncOGT outside of TPR by using Q-TOF MS. Now we focus on the activities and function of ncOGT by mutagenesis studies. This ongoing effort would give us clear understanding of the key enzyme of O-GlcNAc metabolism and how the O-GlcNAc modification may be regulated.