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Li J, Li Z, Duan X, Qin K, Dang L, Sun S, Cai L, Hsieh-Wilson LC, Wu L, Yi W. An Isotope-Coded Photocleavable Probe for Quantitative Profiling of Protein O-GlcNAcylation. ACS chemical biology 2019 14(1) 30620550
Abstract:
O-linked N-acetylglucosamine ( O-GlcNAc) is a ubiquitous post-translational modification of proteins and is essential for cell function. Quantifying the dynamics of O-GlcNAcylation in a proteome-wide level is critical for uncovering cellular mechanisms and functional roles of O-GlcNAcylation in cells. Here, we develop an isotope-coded photocleavable probe for profiling protein O-GlcNAcylation dynamics using quantitative mass spectrometry-based proteomics. This probe enables selective tagging and isotopic labeling of O-GlcNAcylated proteins in one step from complex cellular mixtures. We demonstrate the application of the probe to quantitatively profile O-GlcNAcylation sites in 293T cells upon chemical induction of O-GlcNAc levels. We further applied the probe to quantitatively analyze the stoichiometry of O-GlcNAcylation between sorafenib-sensitive and sorafenib-resistant liver cancer cells, which lays the foundation for mechanistic investigation of O-GlcNAcylation in regulating cancer chemoresistance. Thus, this probe provides a powerful tool to profile O-GlcNAcylation dynamics in cells.
O-GlcNAc proteins:
A0A0B4J203, A0A0C4DFX4, SBNO1, P121B, CX028, RGPD3, AN36A, P121C, GG6L6, S31C2, E9PCH4, H0YAE9, H0YHG0, GG6LV, H3BMH7, PDLI1, TAF4, BCL9, ABLM1, CHD2, KMT2D, RGPD8, OPLA, HGS, MYPT1, ZN609, SC16A, SET1A, TIF1A, EIF3H, TET3, M3K7, PRPF3, TPD54, IF4G3, E41L2, AKAP8, TM11D, MYPT2, GANP, PLIN3, MAFK, BRD4, MITF, N4BP1, ATG13, PP6R2, ANR17, NCOR1, SPAG7, SRS10, SF3B1, CSDE1, TOX4, PCF11, AGFG2, SMC2, M3K6, SC24B, ZBT11, CNOT4, EYA4, OXSR1, ZMYM6, CCNE2, ANGT, LMNA, ALDOA, GCR, HSPB1, F13B, RLA2, K1C18, K2C8, ZFY, SRPRA, RU17, VIME, RU2A, ATX1L, RGPD1, S31C1, GLI3, LYAG, PABP1, COBA1, CO6A3, MYH7, ENPL, ZEP1, RS2, ZFX, ZNF30, ANPRC, ATF7, EGR1, SON, RCC1, ATF1, ATF6A, HXA5, ROA2, CBL, IF4B, GATA2, RIR1, RAE1, APC, ATPA, ARNT, MAP4, HXD9, HLAF, CLIP1, ZEP2, MYH10, TIE1, NU214, DEK, PDE6B, SRP14, CUX1, LPPRC, GATA4, KI67, YAP1, RFX5, SOX2, PRC2A, NASP, CDK8, NU153, RBP2, TAF6, EMD, PAPOA, HCFC1, NEK4, AGFG1, NUP98, INHBC, CADH6, F193A, KGD4, RT34, SARNP, LACTB, COG7, FOXK1, DAB2, PLIN5, SPTB2, SP2, NRG1, IF4G1, K1C17, TLE1, TLE3, TLE4, UBE3A, ACK1, AHNK, FCHO2, FOXO1, TROAP, BPTF, IRAG2, BFSP1, FOXC1, PRDM2, DDX10, G3BP1, PABP4, GRB10, PPIG, MADCA, PICAL, MAMD1, CUL4B, ASPP2, SPTN1, CDK13, CYLC2, DSG2, UBP2L, SRC8, ITPR3, PUM1, MDC1, EPN4, RRP1B, NCOA6, RRP5, RFTN1, R3HD1, WDR43, EEA1, MTFR1, SF3B3, RYR3, SF01, JHD2C, ELF2, MYLK, TAB1, ZYX, ADRM1, QSER1, CL16A, RHG31, AAK1, TMM44, AMOT, IF44L, YIF1B, AG10A, CD048, FSIP2, ESCO1, S2553, BCORL, AN36C, MTUS2, PRC2B, CEP78, SAMD9, TSBP1, LRIF1, CXG2, SKT, ZN648, UBAP2, RBM26, RC3H1, EFCB6, CE350, RPRD2, S31A6, TASO2, ECM29, RN123, PLCX3, ARID2, DEN2C, K0930, LIN54, M18BP, SCYL2, NFRKB, KLH35, ZC3HE, ANR11, FIP1, SBSN, S49A3, FAT4, MCAF1, BCOR, DUSTY, GGYF2, BNC2, CO039, SRCAP, UBN2, FOXNB, UBP54, HAKAI, ASXL2, KNDC1, SPT6H, TAOK1, KDM3B, RGPD4, POGZ, NUFP2, EMSY, I2BP2, SH3R1, HUWE1, YTHD3, FLIP1, KAISO, MYPN, TTC6, LDB1, TM135, TBC26, ZFHX4, ANGL5, SPAS2, DZIP1, P66A, AHNK2, FMNL3, NAV2, ARI3B, MGAP, RP1L1, CC28A, Z3H7A, CDAN1, ANKH1, SUGP1, PHAR4, KMT2E, XRN1, SPART, NUP93, ZN687, CMTR1, THMS1, AN36B, TMTC2, SYNPO, FNBP4, GG6L1, ENAH, GG6L2, SLAI1, PHC3, BD1L1, NUP35, DDX55, NEIL3, GSDMB, ALMS1, STK35, GEMI5, RPGF6, SMCR8, WIPF2, TM171, RN133, TEKT4, LMO7, CKAP2, ATX2L, ACO11, P66B, DAAF4, BBX, FIG4, ZN516, RREB1, FUBP2, LPP, E2F7, TTC28, TOM6, ASTRA, OTUB2, PGBD4, LEG12, ELP4, RBM33, MYEOV, SMRD1, DDX27, P121A, TONSL, PDLI5, THOC3, VCIP1, LRIQ1, ZFR, EP400, CBPC4, RBM14, IPP2L, QKI, PLIN4, JMJD8, RBM15, MINT, SEC62, AGAP2, RGPD5, ATX2, MYD88, ARI3A, SPI2A, SPI2B, DPH2, MCMBP, TMPSD, YTHD1, WNK3, PP12C, TB182, TANC1, CEP44, SENP6, BRD8, RGAP1, ALX4, KI13A, KCNH6, ZN106, FOXP1, PABP3, SMOC2, WNK1, ZHX3, CP095, REEP4, DOCK5, ZN703, GORS2, MLXIP, PKHA5, FOH1B, RC3H2, TANC2, TRPM3, SYTL2, CP4FC, GAK5, JPH1, APMAP, DMAP1, GP108, KMT5A, GPR84, DUOX2, DUOX1, PCDBG, MDN1, NALP2, CARF, HXC10, TAB2, CDK12, ADA2, ITSN2, F135A, SI1L2, RBM27, KANL3, ZN219, DYH17, AFF4, NB5R1, S30BP, NRBP, BAZ2A, SIX4, HOOK1, TASOR, GMEB2, ZHX1, TAOK2, CFA92, MRTFB, ZBT21, PRR12, YETS2, HECD1, MYO6, ICAM5, MAGD2, SCAF8, TRAK1, SHAN2, SRRM2, EXO1, SCML2, POK19, POLH, NCKP1, AT11B, NOP58, ZN281, UB2J1, GRIP1, SALL2, ARIP4, RPGF2, HYOU1, TTLL3, PRC2C, PCDB4, NCOR2, CP46A, 5MP1, CABIN, NCOA3, S23IP, U3KPZ7
Species: Homo sapiens
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Li X, Zhu Q, Shi X, Cheng Y, Li X, Xu H, Duan X, Hsieh-Wilson LC, Chu J, Pelletier J, Ni M, Zheng Z, Li S, Yi W. O-GlcNAcylation of core components of the translation initiation machinery regulates protein synthesis. Proceedings of the National Academy of Sciences of the United States of America 2019 116(16) 30940748
Abstract:
Protein synthesis is essential for cell growth, proliferation, and survival. Protein synthesis is a tightly regulated process that involves multiple mechanisms. Deregulation of protein synthesis is considered as a key factor in the development and progression of a number of diseases, such as cancer. Here we show that the dynamic modification of proteins by O-linked β-N-acetyl-glucosamine (O-GlcNAcylation) regulates translation initiation by modifying core initiation factors eIF4A and eIF4G, respectively. Mechanistically, site-specific O-GlcNAcylation of eIF4A on Ser322/323 disrupts the formation of the translation initiation complex by perturbing its interaction with eIF4G. In addition, O-GlcNAcylation inhibits the duplex unwinding activity of eIF4A, leading to impaired protein synthesis, and decreased cell proliferation. In contrast, site-specific O-GlcNAcylation of eIF4G on Ser61 promotes its interaction with poly(A)-binding protein (PABP) and poly(A) mRNA. Depletion of eIF4G O-GlcNAcylation results in inhibition of protein synthesis, cell proliferation, and soft agar colony formation. The differential glycosylation of eIF4A and eIF4G appears to be regulated in the initiation complex to fine-tune protein synthesis. Our study thus expands the current understanding of protein synthesis, and adds another dimension of complexity to translational control of cellular proteins.
O-GlcNAc proteins:
IF4A1, IF4G1
Species: Homo sapiens
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Darabedian N, Thompson JW, Chuh KN, Hsieh-Wilson LC, Pratt MR. Optimization of Chemoenzymatic Mass Tagging by Strain-Promoted Cycloaddition (SPAAC) for the Determination of O-GlcNAc Stoichiometry by Western Blotting. Biochemistry 2018 57(40) 30169966
Abstract:
The dynamic modification of intracellular proteins by O-linked β -N-acetylglucosamine (O-GlcNAcylation) plays critical roles in many cellular processes. Although various methods have been developed for O-GlcNAc detection, there are few techniques for monitoring glycosylation stoichiometry and state (i.e., mono-, di-, etc., O-GlcNAcylated). Measuring the levels of O-GlcNAcylation on a given substrate protein is important for understanding the biology of this critical modification and for prioritizing substrates for functional studies. One powerful solution to this limitation involves the chemoenzymatic installation of polyethylene glycol polymers of defined molecular mass onto O-GlcNAcylated proteins. These "mass tags" produce shifts in protein migration during sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) that can be detected by Western blotting. Broad adoption of this method by the scientific community has been limited, however, by a lack of commercially available reagents and well-defined protein standards. Here, we develop a "click chemistry" approach to this method using entirely commercial reagents and confirm the accuracy of the approach using a semisynthetic O-GlcNAcylated protein. Our studies establish a new, expedited experimental workflow and standardized methods that can be readily utilized by non-experts to quantify the O-GlcNAc stoichiometry and state on endogenous proteins in any cell or tissue lysate.
O-GlcNAc proteins:
CREB1, NUP62, NED4L
Species: Homo sapiens
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Ramakrishnan P, Clark PM, Mason DE, Peters EC, Hsieh-Wilson LC, Baltimore D. Activation of the transcriptional function of the NF-κB protein c-Rel by O-GlcNAc glycosylation. Science signaling 2013 6(290) 23982206
Abstract:
The transcription factor nuclear factor κB (NF-κB) rapidly reprograms gene expression in response to various stimuli, and its activity is regulated by several posttranslational modifications, including phosphorylation, methylation, and acetylation. The addition of O-linked β-N-acetylglucosamine (a process known as O-GlcNAcylation) is an abundant posttranslational modification that is enhanced in conditions such as hyperglycemia and cellular stress. We report that the NF-κB subunit c-Rel is modified and activated by O-GlcNAcylation. We identified serine 350 as the site of O-GlcNAcylation, which was required for the DNA binding and transactivation functions of c-Rel. Blocking the O-GlcNAcylation of this residue abrogated c-Rel-mediated expression of the cytokine-encoding genes IL2, IFNG, and CSF2 in response to T cell receptor (TCR) activation, whereas increasing the extent of O-GlcNAcylation of cellular proteins enhanced the expression of these genes. TCR- or tumor necrosis factor (TNF)-induced expression of other NF-κB target genes, such as NFKBIA (which encodes IκBα) and TNFAIP3 (which encodes A20), occurred independently of the O-GlcNAcylation of c-Rel. Our findings suggest a stimulus-specific role for hyperglycemia-induced O-GlcNAcylation of c-Rel in promoting T cell-mediated autoimmunity in conditions such as type 1 diabetes by enhancing the production of T helper cell cytokines.
O-GlcNAc proteins:
REL
Species: Homo sapiens
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Yi W, Clark PM, Mason DE, Keenan MC, Hill C, Goddard WA 3rd, Peters EC, Driggers EM, Hsieh-Wilson LC. Phosphofructokinase 1 glycosylation regulates cell growth and metabolism. Science (New York, N.Y.) 2012 337(6097) 22923583
Abstract:
Cancer cells must satisfy the metabolic demands of rapid cell growth within a continually changing microenvironment. We demonstrated that the dynamic posttranslational modification of proteins by O-linked β-N-acetylglucosamine (O-GlcNAcylation) is a key metabolic regulator of glucose metabolism. O-GlcNAcylation was induced at serine 529 of phosphofructokinase 1 (PFK1) in response to hypoxia. Glycosylation inhibited PFK1 activity and redirected glucose flux through the pentose phosphate pathway, thereby conferring a selective growth advantage on cancer cells. Blocking glycosylation of PFK1 at serine 529 reduced cancer cell proliferation in vitro and impaired tumor formation in vivo. These studies reveal a previously uncharacterized mechanism for the regulation of metabolic pathways in cancer and a possible target for therapeutic intervention.
O-GlcNAc proteins:
PFKAM, PFKAL, PFKAP
Species: Homo sapiens
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Rexach JE, Clark PM, Mason DE, Neve RL, Peters EC, Hsieh-Wilson LC. Dynamic O-GlcNAc modification regulates CREB-mediated gene expression and memory formation. Nature chemical biology 2012 8(3) 22267118
Abstract:
The transcription factor cyclic AMP-response element binding protein (CREB) is a key regulator of many neuronal processes, including brain development, circadian rhythm and long-term memory. Studies of CREB have focused on its phosphorylation, although the diversity of CREB functions in the brain suggests additional forms of regulation. Here we expand on a chemoenzymatic strategy for quantifying glycosylation stoichiometries to characterize the functional roles of CREB glycosylation in neurons. We show that CREB is dynamically modified with an O-linked β-N-acetyl-D-glucosamine sugar in response to neuronal activity and that glycosylation represses CREB-dependent transcription by impairing its association with CREB-regulated transcription coactivator (CRTC; also known as transducer of regulated CREB activity). Blocking glycosylation of CREB alters cellular function and behavioral plasticity, enhancing both axonal and dendritic growth and long-term memory consolidation. Our findings demonstrate a new role for O-glycosylation in memory formation and provide a mechanistic understanding of how glycosylation contributes to critical neuronal functions. Moreover, we identify a previously unknown mechanism for the regulation of activity-dependent gene expression, neural development and memory.
O-GlcNAc proteins:
CREB1, CREB1
Species: Rattus norvegicus, Mus musculus
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Rexach JE, Rogers CJ, Yu SH, Tao J, Sun YE, Hsieh-Wilson LC. Quantification of O-glycosylation stoichiometry and dynamics using resolvable mass tags. Nature chemical biology 2010 6(9) 20657584
Abstract:
Mechanistic studies of O-GlcNAc glycosylation have been limited by an inability to monitor the glycosylation stoichiometries of proteins obtained from cells. Here we describe a powerful method to visualize the O-GlcNAc-modified protein subpopulation using resolvable polyethylene glycol mass tags. This approach enables rapid quantification of in vivo glycosylation levels on endogenous proteins without the need for protein purification, advanced instrumentation or expensive radiolabels. In addition, it establishes the glycosylation state (for example, mono-, di-, tri-) of proteins, providing information regarding overall O-GlcNAc site occupancy that cannot be obtained using mass spectrometry. Finally, we apply this strategy to rapidly assess the complex interplay between glycosylation and phosphorylation and discover an unexpected reverse 'yin-yang' relationship on the transcriptional repressor MeCP2 that was undetectable by traditional methods. We anticipate that this mass-tagging strategy will advance our understanding of O-GlcNAc glycosylation, as well as other post-translational modifications and poorly understood glycosylation motifs.
O-GlcNAc proteins:
SP1, SYN1, CREB1, NUP62, MECP2, SYN2, OGA, GORS2
Species: Homo sapiens, Rattus norvegicus
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Wang Z, Park K, Comer F, Hsieh-Wilson LC, Saudek CD, Hart GW. Site-specific GlcNAcylation of human erythrocyte proteins: potential biomarker(s) for diabetes. Diabetes 2009 58(2) 18984734
Abstract:
O-linked N-acetylglucosamine (O-GlcNAc) is upregulated in diabetic tissues and plays a role in insulin resistance and glucose toxicity. Here, we investigated the extent of GlcNAcylation on human erythrocyte proteins and compared site-specific GlcNAcylation on erythrocyte proteins from diabetic and normal individuals.
O-GlcNAc proteins:
PHAR2, ATRN, AL1A1, CAH1, CAH2, HBD, SPTA1, B3AT, CATA, G3P, HS90A, GTR1, EPB41, PYGM, SPTB1, HEM2, ACPH, ANK1, EPB42, PSA5, AQP1, PRDX2, SYUA, HBB, HBA, GSTO1, PRDX1, NOM1, KCD18, VP13B, S29A1, S22AD
Species: Homo sapiens
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Clark PM, Dweck JF, Mason DE, Hart CR, Buck SB, Peters EC, Agnew BJ, Hsieh-Wilson LC. Direct in-gel fluorescence detection and cellular imaging of O-GlcNAc-modified proteins. Journal of the American Chemical Society 2008 130(35) 18683930
Abstract:
We report an advanced chemoenzymatic strategy for the direct fluorescence detection, proteomic analysis, and cellular imaging of O-GlcNAc-modified proteins. O-GlcNAc residues are selectively labeled with fluorescent or biotin tags using an engineered galactosyltransferase enzyme and [3 + 2] azide-alkyne cycloaddition chemistry. We demonstrate that this approach can be used for direct in-gel detection and mass spectrometric identification of O-GlcNAc proteins, identifying 146 novel glycoproteins from the mammalian brain. Furthermore, we show that the method can be exploited to quantify dynamic changes in cellular O-GlcNAc levels and to image O-GlcNAc-glycosylated proteins within cells. As such, this strategy enables studies of O-GlcNAc glycosylation that were previously inaccessible and provides a new tool for uncovering the physiological functions of O-GlcNAc.
O-GlcNAc proteins:
A0A0G2JYI7, A0A0G2K931, A0A0G2KAS9, ROA2, OTUB1, SEP11, B5DFG5, D3ZM69, HCFC1, D3ZQM0, D3ZUY8, D3ZVQ0, D4A0B4, D4A133, D4A1L2, D4A554, D4AA63, D4ABT8, D4ACB8, E9PT29, E9PTR4, S2512, RPGF2, F1M3L4, F1M3W5, F1M7Y3, F1M8R0, F1M949, F1M9V7, G3V7M0, G3V8Q8, HNRPC, SERA, AMPH, DCLK1, NCDN, CTND2, DNM1L, PICAL, CLIP2, ANK3, PACS1, HSP74, BSN, PTN23, AATM, CRYAA, ROA1, ENOA, HXK1, ENOG, ODP2, ALDOC, GLNA, SYN1, SORL, PLCB1, ATPB, DHE3, KCC2A, AT2A2, PDIA3, KPYM, FAS, AATC, MTAP2, MAP1B, ATPA, SPTN1, PGK1, HMCS1, AP2A2, CSK21, PO3F1, DYN1, MK03, AINX, THOP1, PGAM1, VPP1, ODPA, DCTN1, MARCS, MAP1A, 1433B, DYHC1, TERA, RP3A, PFKAM, PFKAP, ANXA6, TPIS, ODPB, NU153, GDIA, HUWE1, PYGB, GBB1, SNAA, NCKP1, OGT1, ACTB, HNRPK, 1433G, RS8, 1433E, RL7A, EF1A1, ACTA, VATB2, RS3, AP2B1, CH60, RACK1, PP2BA, KAPCB, 1433T, EF2K, VDAC2, GNAQ, TBB2A, FSCN1, ARPC2, CAND1, AP180, ADT1, ANXA2, ADT2, MYPT1, MIC60, TBB2B, CARM1, SRPRB, RD23B, TBB3, RBMX, OXR1, Q4V8F6, ZFR, WASF1, E41L5, RUFY3, DTBP1, SHLB2, Q5RJQ1, WDR1, IF4A2, CAPZB, ODO1, TBA4A, TCPB, SPTB2, 4EBP1, CAPS1, SYNJ1, DPYL1, DPYL4, DPYL3, CAMKV, KCC1A, MAP6, NDUS2, BACH, HS105, NDUS1, MAVS, PURB, QCR1, Q6AY07, Q6AYI1,