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Bi Y, Deng Z, Ni W, Shrestha R, Savage D, Hartwig T, Patil S, Hong SH, Zhang Z, Oses-Prieto JA, Li KH, Quail PH, Burlingame AL, Xu SL, Wang ZY. Arabidopsis ACINUS is O-glycosylated and regulates transcription and alternative splicing of regulators of reproductive transitions. Nature communications 2021 12(1) 33574257
Abstract:
O-GlcNAc modification plays important roles in metabolic regulation of cellular status. Two homologs of O-GlcNAc transferase, SECRET AGENT (SEC) and SPINDLY (SPY), which have O-GlcNAc and O-fucosyl transferase activities, respectively, are essential in Arabidopsis but have largely unknown cellular targets. Here we show that AtACINUS is O-GlcNAcylated and O-fucosylated and mediates regulation of transcription, alternative splicing (AS), and developmental transitions. Knocking-out both AtACINUS and its distant paralog AtPININ causes severe growth defects including dwarfism, delayed seed germination and flowering, and abscisic acid (ABA) hypersensitivity. Transcriptomic and protein-DNA/RNA interaction analyses demonstrate that AtACINUS represses transcription of the flowering repressor FLC and mediates AS of ABH1 and HAB1, two negative regulators of ABA signaling. Proteomic analyses show AtACINUS's O-GlcNAcylation, O-fucosylation, and association with splicing factors, chromatin remodelers, and transcriptional regulators. Some AtACINUS/AtPININ-dependent AS events are altered in the sec and spy mutants, demonstrating a function of O-glycosylation in regulating alternative RNA splicing.
O-GlcNAc proteins:
A0A384LHA9
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Wang J, Wang Z, Yuan J, Wang J, Shen X. The positive feedback between ACSL4 expression and O-GlcNAcylation contributes to the growth and survival of hepatocellular carcinoma. Aging 2020 12(9) 32357142
Abstract:
Acyl-CoA ligase 4 (ACSL4) has been reported to be overexpressed in hepatocellular carcinoma (HCC) and to enhance cell proliferation. However, the molecular mechanisms underlying the role of ACSL4 in HCC progression remain largely unclear. Here, we aimed to investigate whether and how O-GlcNAcylation and ACSL4 regulate each other and HCC progression. The clinical significance of ACSL4, O-GlcNAc and GLUT1 in HCC was determined by Pearson chi-squared test and Kaplan-Meier analysis. CCK-8, flow cytometry and in vivo tumour formation assays were performed to detect cell proliferation, apoptosis and tumorigenesis. IP technology was used to evaluate the relationship between ACSL4 and O-GlcNAc. ACSL4, GLUT1 and O-GlcNAc levels were elevated in HCC tissues and predicted poor prognosis in HCC patients. ACSL4 overexpression significantly promoted cell proliferation and tumorigenesis and inhibited cell apoptosis, whereas these effects were all obviously impaired when mTOR signalling was repressed or GLUT1 was downregulated. ACSL4 could be O-GlcNAcylated, and silencing of ACSL4 abolished the effects of O-GlcNAcylation on cell growth promotion and apoptosis inhibition. Collectively, this study demonstrates that ACSL4 contributes to the growth and survival of HCC by enhancing GLUT1-mediated O-GlcNAcylation. In turn, O-GlcNAcylation promotes HCC growth partially by increasing ACSL4 expression.
O-GlcNAc proteins:
ACSL4
Species: Homo sapiens
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Wang Z, Qin J, Zhao J, Li J, Li D, Popp M, Popp F, Alakus H, Kong B, Dong Q, Nelson PJ, Zhao Y, Bruns CJ. Inflammatory IFIT3 renders chemotherapy resistance by regulating post-translational modification of VDAC2 in pancreatic cancer. Theranostics 2020 10(16) 32641986
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide and effective therapy remains a challenge. IFIT3 is an interferon-stimulated gene with antiviral and pro-inflammatory functions. Our previous work has shown that high expression of IFIT3 is correlated with poor survival in PDAC patients who receive chemotherapy suggesting a link between IFIT3 and chemotherapy resistance in PDAC. However, the exact role and molecular mechanism of IFIT3 in chemotherapy resistance in PDAC has been unclear. Methods: A group of transcriptome datasets were downloaded and analyzed for the characterization of IFIT3 in PDAC. Highly metastatic PDAC cell line L3.6pl and patient-derived primary cell TBO368 were used and IFIT3 knockdown and the corresponding knockin cells were established for in vitro studies. Chemotherapy-induced apoptosis, ROS production, confocal immunofluorescence, subcellular fractionation, chromatin-immunoprecipitation, co-immunoprecipitation and mass spectrometry analysis were determined to further explore the biological role of IFIT3 in chemotherapy resistance of PDAC. Results: Based on PDAC transcriptome data, we show that IFIT3 expression is associated with the squamous molecular subtype of PDAC and an increase in inflammatory response and apoptosis pathways. We further identify a crucial role for IFIT3 in the regulation of mitochondria-associated apoptosis during chemotherapy. Knockdown of IFIT3 attenuates the chemotherapy resistance of PDAC cells to gemcitabine, paclitaxel, and FOLFIRINOX regimen treatments, independent of individual chemotherapy regimens. While IFIT3 overexpression was found to promote drug resistance. Co-immunoprecipitation identified a direct interaction between IFIT3 and the mitochondrial channel protein VDAC2, an important regulator of mitochondria-associated apoptosis. It was subsequently found that IFIT3 regulates the post-translational modification-O-GlcNAcylation of VDAC2 by stabilizing the interaction of VDAC2 with O-GlcNAc transferase. Increased O-GlcNAcylation of VDAC2 protected PDAC cells from chemotherapy induced apoptosis. Conclusions: These results effectively demonstrate a central mechanism by which IFIT3 expression can affect chemotherapy resistance in PDAC. Targeting IFIT3/VDAC2 may represent a novel strategy to sensitize aggressive forms of pancreatic cancer to conventional chemotherapy regimens.
O-GlcNAc proteins:
VDAC2
Species: Homo sapiens
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Xu SL, Chalkley RJ, Maynard JC, Wang W, Ni W, Jiang X, Shin K, Cheng L, Savage D, Hühmer AF, Burlingame AL, Wang ZY. Proteomic analysis reveals O-GlcNAc modification on proteins with key regulatory functions in Arabidopsis. Proceedings of the National Academy of Sciences of the United States of America 2017 114(8) 28154133
Abstract:
Genetic studies have shown essential functions of O-linked N-acetylglucosamine (O-GlcNAc) modification in plants. However, the proteins and sites subject to this posttranslational modification are largely unknown. Here, we report a large-scale proteomic identification of O-GlcNAc-modified proteins and sites in the model plant Arabidopsis thaliana Using lectin weak affinity chromatography to enrich modified peptides, followed by mass spectrometry, we identified 971 O-GlcNAc-modified peptides belonging to 262 proteins. The modified proteins are involved in cellular regulatory processes, including transcription, translation, epigenetic gene regulation, and signal transduction. Many proteins have functions in developmental and physiological processes specific to plants, such as hormone responses and flower development. Mass spectrometric analysis of phosphopeptides from the same samples showed that a large number of peptides could be modified by either O-GlcNAcylation or phosphorylation, but cooccurrence of the two modifications in the same peptide molecule was rare. Our study generates a snapshot of the O-GlcNAc modification landscape in plants, indicating functions in many cellular regulation pathways and providing a powerful resource for further dissecting these functions at the molecular level.
O-GlcNAc proteins:
A0A178U7T2, A0A178U808, A0A178U8C4, A0A178U9U2, A0A178UA87, A0A178UAK4, A0A178UBS4, A0A178UEJ0, A0A178UET6, A0A178UG83, A0A178UGM3, A0A178UJQ0, A0A178UKB4, A0A178ULB6, A0A178UM22, A0A178UNF9, A0A178UTT8, A0A178UVW2, A0A178UW70, A0A178UXN3, A0A178UZJ4, A0A178V3S5, A0A178V4Y0, A0A178V7N5, A0A178V7S6, A0A178V9D9, A0A178VCA9, A0A178VF25, A0A178VGI0, A0A178VGK7, A0A178VIB4, A0A178VL84, A0A178VMH9, A0A178VN08, A0A178VNI5, A0A178VQ37, A0A178VQ53, A0A178VQY8, A0A178VS21, A0A178VTI3, A0A178VTN0, A0A178VUZ4, A0A178VWA9, A0A178VXV2, A0A178VZ34, A0A178W0U1, A0A178W4Q8, A0A178W585, A0A178W9L4, A0A178WAQ6, A0A178WCT2, A0A178WD70, A0A178WK45, A0A178WKM1, A0A1I9LM16, A0A1I9LM89, A0A1I9LNN0, A0A1I9LPG3, A0A1I9LPZ1, A0A1I9LQ18, A0A1I9LQ49, A0A1I9LQK5, A0A1I9LR14, A0A1I9LR16, A0A1I9LRR1, A0A1I9LRS8, A0A1I9LT31, A0A1I9LT54, A0A1I9LT69, A0A1I9LTD0, A0A1I9LTD1, A0A1I9LTL7, A0A1I9LTL8, A0A1I9LTL9, A0A1P8AM87, A0A1P8ANR5, A0A1P8APV6, A0A1P8APZ6, A0A1P8AQ08, A0A1P8AQI9, A0A1P8AQR8, A0A1P8ARB7, A0A1P8ARJ2, A0A1P8ARU4, A0A1P8ARV7, A0A1P8ARV8, A0A1P8AS00, ECT4, A0A1P8AS28, A0A1P8ASD0, A0A1P8ASK1, A0A1P8ASQ6, A0A1P8AT85, A0A1P8ATA1, A0A1P8ATG6, A0A1P8AUP4, A0A1P8AUP7, A0A1P8AWC8, A0A1P8AXG2, A0A1P8AXN6, A0A1P8AXY9, A0A1P8AYH5, A0A1P8AYN4, A0A1P8B0K6, A0A1P8B0M2, A0A1P8B1D0, A0A1P8B1H7, A0A1P8B1J3, A0A1P8B1N0, A0A1P8B1N9, A0A1P8B1P6, A0A1P8B1P9, A0A1P8B2G0, A0A1P8B2Y3, A0A1P8B4Z4, A0A1P8B569, A0A1P8B6K1, A0A1P8B6K2, A0A1P8B739, A0A1P8B753, A0A1P8B770, A0A1P8B7E4, A0A1P8B7F4, A0A1P8B889, A0A1P8B895, A0A1P8B8G6, A0A1P8B9E0, A0A1P8B9Q7, A0A1P8B9R0, A0A1P8BAL0, A0A1P8BBS5, A0A1P8BBU0, A0A1P8BBV1, A0A1P8BBW1, A0A1P8BCJ2, A0A1P8BCM2, A0A1P8BCS5, A0A1P8BDJ5, A0A1P8BDM9, A0A1P8BES5, A0A1P8BET4, A0A1P8BF20, A0A1P8BF26, A0A1P8BF50, A0A1P8BFA1, A0A1P8BFW7, A0A1P8BGW8, A0A2H1ZEI5, A0A2H1ZEK0, A0A384KDE2, A0A384KK08, A0A384KLV2, A0A384KRL7, A0A384L4P3, A0A384LCJ3, A0A384LD93, A0A384LHA9, A0A384LIC3, A0A384LL64, NSRA, GIP1L, A4FVS4, A8MPR6, A8MQK8, A8MQL9, A8MR17, A8MR45, A8MR97, SMG7, B3H4M3, NEDD1, B3H6D1, B3H7F6, B3H7M2, B6DT55, B9DH05, SP13A, C0Z2N6, C0Z387, SUV2, F4HNU1, F4HPG4, F4HSW8, F4HVV6, F4HVV7, F4HWS5, F4HXP0, F4HY32, F4I0C1, F4I0C2, F4I1G1, NP214, F4I2D0, RB47A, F4I4I8, F4I982, F4I983, F4IC79, PHL, F4IGJ9, F4IHK9, SYD, F4IIR1, FLX, F4IMY0, RSA1, F4IWD6, F4J043, PATH1, F4J0L7, F4J0P2, F4J7C7, VIR, F4J912, SAC3B, F4JB30, F4JDC2, F4JDC3, F4JDC5, F4JFN7, F4JKV2, F4JLR7, F4JP43, F4JPL0, F4JPL1, F4JPL2, F4JRD9, F4JUD2, F4JV21, F4JWJ6, F4JWJ7, F4JWP8, F4JXH8, PIAL2, F4K3D6, F4K3Y7, F4K402, F4K465, F4K4Y6, F4K5M5, STKLU, F4K9A6, CHR4, F4KDJ9, F4KDM9, HEN4, F4KDN1, SRC2, FCA, PABP4, AHL10, O23146, IF4E1, NFYB3, O48697, O48807, LUH, AHL2, O64768, CID7, CAB25, TOL6, O81015, O82263, NGA4, NGA1, KNAT3, DRMH1, ARFG, C3H30, RBG7, QKIL1, Q0WP31, PAT1H, Q0WQD5, Q0WTU8, Q0WUK0, Q0WUY5, TBA4, Q0WVJ1, SLK1, Q1G3K2, Q1JPL5, TPR4, LUMI, AGL11, Q3EDL2, DOF37, MED8, Q56W68, Q56WR5, Q56WT6, Q56X31, Q56YP1, Q56YR0, C3H67, Q66GK1, EPN2, BRM, Q6ID24, FY, Q6NM13, Q6RF52, WOX4, IDD10, IF4G, MED25, DOF18, Q84TH3, C3H32, Q84WZ4, CTF77, SPL8, TGH, C3H33, Q8GYC9, QKIL4, Q8GYU8, Q8GZ14, KTN84, Q8H1P8, CID3, AHL11, Q8L9Z3, DOF46, RL51, RLA11, DOF54, Q8LFT9, CPL3, Q8LPI8, FPA, LRP1B, Q8RWV9, AGD14, ARFS, GEM, AML5, Q8VY17, Q8VYH3, AHL1, Q8VYZ1, Q8VZL1, Q8VZM2, GIP1, RNP1, SEUSS, AML1, Q8W4K6, Q8W569, IF5A2, WRK20, Q93XY1, EPN3, Q93YU3, TCP14, Q93ZW3, TA12B, AHL13, Q940N4, Q940N7, C3H37, Q949Z3, TPL, SLK2, PATH2, C3H55, LRP1C, TIC, SPY, TCP8, Q9C584, MPK18, HAC1, Q9C7A7, Q9C7W1, TRO, SCY2B, Y3857, NUP1, Y1385, Q9FF08, ARFH, Q9FH07, FLXL4, DCP5L, Q9FHN1, Q9FIA3, ZHD10, Q9FJ56, Q9FJC2, Q9FKL3, ZHD1, QKIL2, SUMO2, Q9FM47, Q9FM71, EXA1, Q9FNB9, C3H51, Q9FPE7, VIP2, XRN4, ZHD5, SPT, LEUNG, HAC12, PABP8, PEX14, SPL11, EIF3A, Q9LDZ8, HAC5, BPA1, ZHD9, C3H38, ECT2, PUM5, UBA2C, Q9LM78, Q9LM88, Q9LNA8, BH013, Q9LP92, Q9LQ83, C3H12, IDD11, TPR2, Q9LSD7, Q9LSK7, VCS, VCR, Q9LVK1, IDD1, ZHD8, C3H56, AML4, Q9LZQ7, BIG2, Q9M0M3, DNMT2, Q9M0Y0, Q9M141, Q9M1E4, RH52, AHL15, Q9M369, AI5L6, Q9M9Z1, TCP3, NGA3, EIN2, SPL2, IF4B2, MOS1, Q9SCK9, C3H44, Q9SD86, Q9SD87, RH45, Q9SFD3, WRKY1, BZP30, C3H19, AML2, Q9SK04, Q9SK05, Q9SKR5, PUR, Q9SN77, RH40, PUM4, PRP8A, C3H43, SPT51, Q9STX4, Q9SU22, Q9SU23, Q9SU99, Q9SUE8, C3H46, NINJA, BLH2, R47CP, Q9SZ51, TCX5, PEP, PCKA1, FB230, ARFF, ARFD, Q9ZU48, IDD5, FRS3, QKIL3, PUM2, PUM1
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Ma YT, Luo H, Guan WJ, Zhang H, Chen C, Wang Z, Li JD. O-GlcNAcylation of BMAL1 regulates circadian rhythms in NIH3T3 fibroblasts. Biochemical and biophysical research communications 2013 431(3) 23337503
Abstract:
Various physiological processes and behaviors show a circadian rhythm of approximately 24 h, which is crucial in coordinating internal metabolic processes and environmental signals. Post-translational modifications play an important role in regulating circadian core proteins. In this study, we demonstrated that BMAL1 was modified with an O-linked β-N-acetylglucosamine (O-GlcNAc), which stabilized BMAL1 and enhanced its transcriptional activity. Conversely, inhibition of O-GlcNAcylation resulted in inhibition of circadian rhythms of clock gene expression. Because O-GlcNAcylation is sensitive to the glucose level, such a modification may provide a new mechanism connecting metabolism with circadian rhythms.
O-GlcNAc proteins:
BMAL1, BMAL1
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Alfaro JF, Gong CX, Monroe ME, Aldrich JT, Clauss TR, Purvine SO, Wang Z, Camp DG 2nd, Shabanowitz J, Stanley P, Hart GW, Hunt DF, Yang F, Smith RD. Tandem mass spectrometry identifies many mouse brain O-GlcNAcylated proteins including EGF domain-specific O-GlcNAc transferase targets. Proceedings of the National Academy of Sciences of the United States of America 2012 109(19) 22517741
Abstract:
O-linked N-acetylglucosamine (O-GlcNAc) is a reversible posttranslational modification of Ser and Thr residues on cytosolic and nuclear proteins of higher eukaryotes catalyzed by O-GlcNAc transferase (OGT). O-GlcNAc has recently been found on Notch1 extracellular domain catalyzed by EGF domain-specific OGT. Aberrant O-GlcNAc modification of brain proteins has been linked to Alzheimer's disease (AD). However, understanding specific functions of O-GlcNAcylation in AD has been impeded by the difficulty in characterization of O-GlcNAc sites on proteins. In this study, we modified a chemical/enzymatic photochemical cleavage approach for enriching O-GlcNAcylated peptides in samples containing ∼100 μg of tryptic peptides from mouse cerebrocortical brain tissue. A total of 274 O-GlcNAcylated proteins were identified. Of these, 168 were not previously known to be modified by O-GlcNAc. Overall, 458 O-GlcNAc sites in 195 proteins were identified. Many of the modified residues are either known phosphorylation sites or located proximal to known phosphorylation sites. These findings support the proposed regulatory cross-talk between O-GlcNAcylation and phosphorylation. This study produced the most comprehensive O-GlcNAc proteome of mammalian brain tissue with both protein identification and O-GlcNAc site assignment. Interestingly, we observed O-β-GlcNAc on EGF-like repeats in the extracellular domains of five membrane proteins, expanding the evidence for extracellular O-GlcNAcylation by the EGF domain-specific OGT. We also report a GlcNAc-β-1,3-Fuc-α-1-O-Thr modification on the EGF-like repeat of the versican core protein, a proposed substrate of Fringe β-1,3-N-acetylglucosaminyltransferases.
O-GlcNAc proteins:
ZEP3, CAMP1, FRPD1, SKT, DLGP4, DPYL2, STXB1, MAP2, NUMBL, M3K5, NOTC2, CTND2, CSK22, ACK1, SYUA, ATX2, ZFR, BSN, GCR, EGR1, NFL, NFM, RC3H2, MAMD1, ATX1L, DERPC, NCAM1, MAP1B, G3P, ATF2, MAP4, KCC2B, AIMP1, FOXK1, STAT3, AINX, NEDD4, RP3A, DVL1, GOGA3, FOXP1, TB182, GMEB2, PI5PA, MRTFB, DOCK4, ABI2, KCNJ3, NCOA1, RGRF2, TNIK, WNK1, G3BP2, MPRIP, XRN1, RLA2, S30BP, NFIA, MARK3, ENAH, PGBM, CDK12, MA6D1, PHAR1, PSD3, NELL1, PRC2C, YETS2, FOXK2, WNK2, LIMC1, TNR6C, AGAP2, ZEP2, AAK1, TNR6A, CAMKV, PKHA7, GRIN1, FCHO2, GARL3, STOX2, UBN1, ABL2, CDV3, PHAR4, TAB3, NUFP2, UNKL, OSBP2, RBM27, CYFP2, TM1L2, ANR40, NACAD, SIN3A, NCOR1, LAMA5, NCOA2, AP180, RAI1, M3K7, TAF6, SRBS1, SH3G1, TLE4, MINT, ZYX, SF01, SYN2, TBR1, SBNO1, CRTC1, GIT1, SLAI1, PKP4, CDK13, RHG23, SH3R1, JHD2C, HECD1, ABLM3, ARMX2, LAR4B, RHG21, FBX41, RPRD2, WWC2, ZN532, BCR, DLGP3, NYAP1, GMIP, NFRKB, MAGI1, CNOT1, NU188, PICAL, SMAP2, SPAG7, PRC2B, ATX2L, MAP6, MCAF1, PHF24, NAV3, AUXI, RERE, RIMB2, PUM1, NU214, KCMF1, EPN1, AGFG2, UBP2L, C2C2L, CNKR2, ZN598, SHAN2, MAST4, RHG32, MYPT2, TB10B, FRM4A, SP130, DLGP2, ZNT6, ABLM2, EMSY, CLAP2, CNOT4, PAMR1, CREST, IFFO1, OSBL6, YTHD3, TM266, SI1L1, SH3R3, RBM14, CNOT2, ANK2, DIDO1, SYNPO, VCIP1, TAB1, SCYL2, ASPP2, F193A, OGT1, NAV1, SYNJ1, RPGF2, EP400, P66A, PDLI5, SCAM1, HS12A, AGFG1, I2BPL, PO121, ABLM1, SPART, RFIP5, CS047, SIR2, AMOT, CCG8, ZCH14, WDR13, UBAP2, NCOA5, FRS3, ZFN2B, BASP1, DCP1A, SRGP2, SRGP1, SYUB, CLIP1, UBXN1, GORS2, EPN4, RB6I2, ANR17, RTN4, TXD12, NECP1, DLGP1, FIP1, F135B, TM263, PLIN3, MYPT1, CRIP2, TSC1, NBEA, RIMS2, ZN704, RBP2, RTN3, 4ET, ELF2, NUDT3, FMN2, NCOA6, SRCN1, ASAP1, RAD1, SON, PLEC, ULK2, ADDA, PCLO, HIPK2, SH2D3, YLPM1, RHG07, TEN1, NCOR2, COR1B, TNIP1, DEMA, E41L3, SYUG, APCL, MECP2, E41L1
Species: Mus musculus
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Zeidan Q, Wang Z, De Maio A, Hart GW. O-GlcNAc cycling enzymes associate with the translational machinery and modify core ribosomal proteins. Molecular biology of the cell 2010 21(12) 20410138
Abstract:
Protein synthesis is globally regulated through posttranslational modifications of initiation and elongation factors. Recent high-throughput studies have identified translation factors and ribosomal proteins (RPs) as substrates for the O-GlcNAc modification. Here we determine the extent and abundance of O-GlcNAcylated proteins in translational preparations. O-GlcNAc is present on many proteins that form active polysomes. We identify twenty O-GlcNAcylated core RPs, of which eight are newly reported. We map sites of O-GlcNAc modification on four RPs (L6, L29, L32, and L36). RPS6, a component of the mammalian target of rapamycin (mTOR) signaling pathway, follows different dynamics of O-GlcNAcylation than nutrient-induced phosphorylation. We also show that both O-GlcNAc cycling enzymes OGT and OGAse strongly associate with cytosolic ribosomes. Immunofluorescence experiments demonstrate that OGAse is present uniformly throughout the nucleus, whereas OGT is excluded from the nucleolus. Moreover, nucleolar stress only alters OGAse nuclear staining, but not OGT staining. Lastly, adenovirus-mediated overexpression of OGT, but not of OGAse or GFP control, causes an accumulation of 60S subunits and 80S monosomes. Our results not only establish that O-GlcNAcylation extensively modifies RPs, but also suggest that O-GlcNAc play important roles in regulating translation and ribosome biogenesis.
O-GlcNAc proteins:
RS6
Species: Homo sapiens
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Sakabe K, Wang Z, Hart GW. Beta-N-acetylglucosamine (O-GlcNAc) is part of the histone code. Proceedings of the National Academy of Sciences of the United States of America 2010 107(46) 21045127