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Chuh KN, Batt AR, Zaro BW, Darabedian N, Marotta NP, Brennan CK, Amirhekmat A, Pratt MR. The New Chemical Reporter 6-Alkynyl-6-deoxy-GlcNAc Reveals O-GlcNAc Modification of the Apoptotic Caspases That Can Block the Cleavage/Activation of Caspase-8. Journal of the American Chemical Society 2017 139(23) 28528544
Abstract:
O-GlcNAc modification (O-GlcNAcylation) is required for survival in mammalian cells. Genetic and biochemical experiments have found that increased modification inhibits apoptosis in tissues and cell culture and that lowering O-GlcNAcylation induces cell death. However, the molecular mechanisms by which O-GlcNAcylation might inhibit apoptosis are still being elucidated. Here, we first synthesize a new metabolic chemical reporter, 6-Alkynyl-6-deoxy-GlcNAc (6AlkGlcNAc), for the identification of O-GlcNAc-modified proteins. Subsequent characterization of 6AlkGlcNAc shows that this probe is selectively incorporated into O-GlcNAcylated proteins over cell-surface glycoproteins. Using this probe, we discover that the apoptotic caspases are O-GlcNAcylated, which we confirmed using other techniques, raising the possibility that the modification affects their biochemistry. We then demonstrate that changes in the global levels of O-GlcNAcylation result in a converse change in the kinetics of caspase-8 activation during apoptosis. Finally, we show that caspase-8 is modified at residues that can block its cleavage/activation. Our results provide the first evidence that the caspases may be directly affected by O-GlcNAcylation as a potential antiapoptotic mechanism.
O-GlcNAc proteins:
A2A4A6, A2A5R8, GPTC8, SPD2B, A2ACG7, A2AFQ9, A2AFW6, A2AG46, CKAP5, A2AH75, A2AJ72, MA7D1, A2AL12, A2AMW0, A2AMY5, TPX2, PPIG, LAS1L, A5A4Y9, A6PWC3, A6PWK7, UBP36, B1AT03, B1AT82, B1AU75, B2RQG2, OTUD4, B7ZCP4, B7ZP47, D3YUW8, D3YWF6, D3YWK1, D3YX62, SAFB1, D3YXM7, D3YZ06, D3YZP6, D3Z069, D3Z158, D3Z3F8, D3Z6W2, E0CYM1, E9PUH7, E9PVM7, E9PWG6, E9PWV3, E9PWW9, E9PY48, E9PYT3, E9PZM7, E9Q066, E9Q2X6, E9Q3G8, E9Q450, E9Q4K7, E9Q4Q2, KIF23, BD1L1, NUMA1, E9Q7M2, E9Q986, E9Q9E1, E9Q9H2, E9QKG3, E9QKG6, E9QKZ2, E9QLA5, E9QP49, E9QP59, E9QPI5, F2Z3X7, F6S5I0, F7AA26, F7BQE4, FARP1, F8VQ93, F8VQC7, F8VQE9, F8VQK5, F8WI30, G3UZ44, G3UZX6, G3X8R0, G3X8Y3, G3X928, G3X963, G3X972, G3X9V0, G5E896, G5E8E1, H3BJU7, H3BK31, H3BKK2, H7BX26, I1E4X0, I7HIK9, J3QNW0, DPYL2, GTPB1, AKAP1, TCOF, AIP, HDAC1, RL21, GSH0, KIF1C, DHX15, SC6A6, IF6, ILK, ATX2, NMT1, E41L2, DHB12, SRPK1, ZN326, ZFR, PARG, SPD2A, SP1, CASP8, HPRT, LDHA, G6PI, TYSY, RIR1, GNAI2, ITB1, 4F2, H2B1F, MAP1B, HMOX1, LEG1, G3P, KS6A3, COF1, GNAO, IFRD1, VIME, TPM3, UBL4A, CBX3, CXA1, CATA, IMDH2, IL1RA, MCM3, CDK4, NKTR, FKBP4, CBX2, HMGB2, AIMP1, KAP3, MP2K1, SYWC, KIF4, NEDD1, DPOLA, RANG, UBP4, PTN11, RAB18, PTN1, PTN12, LDLR, DNLI1, CAP1, STAT3, STA5B, PURA, ALD2, RAGP1, NEDD4, STT3A, ALDH2, GSHR, GFPT1, PCY1A, MCM4, ICAL, PLCB3, CDN2A, HDGF, UBP10, KPYM, CCHL, IDHP, DDX6, GOGA3, COX17, ACTN4, GCP3, TB182, EIF3E, ABCE1, PFD3, HNRPK, 1433E, RAP1A, RS25, TCTP, DNJA1, HMGB1, IF5A1, RS17, RS12, UB2L3, HXD13, HDAC2, ELAV1, TP53B, CASP3, PYRG1, TCPB, STIM2, SRSF3, CSRP2, SPTC2, BOP1, SMAD4, M4K4, HNRL2, MARK3, LARP7, CNN2, PP4R2, PEPD, CDCA2, Q3TFP0, GUAA, PDE12, Q3TL72, PRC2C, NOL9, FUBP2, TRADD, CTU2, ZN865, Q3U4W8, Q3UG37, NAT9, NOL8, Q3UJQ9, SC31A, NCBP1, LRRF1, DDX17, LRC47, JIP4, EHMT1, CA050, AAPK1, NSRP1, Q5RL57, Q5SQB0, TENS3, PUR4, Q5UE59, SRC8, SAMH1, KHDR1, GRB10, HELLS, SPB6, RIPK1, CAPR1, ASNS, LAP2A, CDC37, TS101, SNTB2, FNTA, BAP31, PLPP1, FSCN1, FXR1, DDX5, ATRX, HS105, DDX3Y, DDX3X, TGFI1, DBNL, SH3G1, CYTB, SMAD2, NDRG1, ZYX, SQSTM, TPP2, ZN512, LAR4B, F120A, CNDG2, NOP58, LTV1, Q6NV52, Q6NXL1, Q6NZD2, ANKL2, Q6P5B5, XPO1, KIF15, FHOD1, TXLNA, PTN23, JUPI2, NUDC1, TACC1, UBE2O, LARP1, ACAP2, 2AAA, MTCH2, ZN503, CYFP1, HNRPQ, SPAG7, DEK, ACTN1, ATX2L, CKP2L, ZN516, ERBIN, SEPT9, PGRC2, Q80VB6, UBP2L, PI42B, ZN598, SAFB2, Q80ZX0, DLG1, LPP, PEF1, IF4B, FTO, TIPRL, Q8BH80, MISSL, ERC6L, CARF, PRUN1, NUP93, FBX30, HBAP1, AHSA1, RCC2, IPO5, SYLC, CKAP4, MAP11, PALM2, CPNE3, SENP7, CSN7B, NSD2, DPP9, Q8BWW3, KANK2, PXK, PIGT, ITPK1, NHLC2, MAP1S, GWL, PKHH2, CND2, THOP1, SEP11, SKA3, CA198, SEP10, AROS, UBA6, LIPB1, SMAG1, Q8CCM0, ZN276, NAA30, SNX8, SYEP, OGT1, GNL3, PDLI5, FERM2, AGO2, HMCS1, AMERL, SCNM1, DNM1L, NEK9, ANLN, EDC3, MATR3, CHAP1, MEPCE, ERF3A, CC137, TDIF2, VPS18, RFC3, MCMBP, HEXI1, LUZP1, SNP47, TMX1, MAVS, UBXN4, Q8VCQ8, ACSF2, PARN, VIGLN, PSMD2, NAA40, F1142, ZNG1, PAXI, SFPQ, CPIN1, RAB14, IPYR2, PUS7, CSDE1, PIP30, RABE2, CISD1, Q91X76, DUS3L, KCC1A, TTC1, SRGP2, SNX18, RISC, HNRLL, Q921K2, PP6R3, LRC59, UBXN1, DBR1, KCC2G, Q924B0, WAC, SMC6, PAWR, SIAS, STML2, PSIP1, NXF1, PDXD1, NONO, PLST, RRAGC, VMA5A, MAOM, DCTN2, ZN281, CT2NL, GRPE1, ABD12, RTN4, NU155, OGFR, NPM3, NOP16, GLOD4, DUT, MTAP, IFM3, CYB5B, PAF15, PSMD9, WIPI3, SKA2, VATG1, CHSP1, LRC40, RANB3, SMC1A, MFR1L, ARHGP, DDX47, TBC15, PPIL4, MPPB, CYBP, TECR, PAIRB, ZCHC8, SPCS2, Q9CZP3, CD37L, SSBP3, MMS19, MGRN1, ARPIN, HNRPM, SYRC, MCES, Q9D4G5, ATAD1, F162A, TRIR, IPYR, PHF10, ARFG3, ORN, BOLA1, CNN3, KAP0, PLIN3, AKAP8, XRN2, GNAI3, PUR6, RAI14, SENP3, ARFG1, SIL1, VPS35, DGCR8, SYCC, ELP4, LIMA1, XPO2, RBP2, RTN3, PALLD, TMOD3, STK3, COPB, NUP50, DDX21, SH3L1, DDX20, MBNL1, BAG3, GKAP1, ZN207, TRXR1, PPCE, CAF1A, LIMD1, NDRG3, DNJC7, NFU1, COPG1, NUBP1, SMAP, DEST, ACOT9, PR40A, FOXO1, FIZ1, NFKB2, KAD2, AKA12, PRKRA, PDC6I, CHIP, COR1C, VAPA, NDKM, E41L3, TAGL2, CARM1, MTNB, BCL10, IF2G, P5CS, COG1, MD2L1, EIF3G, SAE2, ILF3, TRIP6, USO1, BAZ1B, HNRPF, KEAP1
Species: Mus musculus
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Gurel Z, Zaro BW, Pratt MR, Sheibani N. Identification of O-GlcNAc modification targets in mouse retinal pericytes: implication of p53 in pathogenesis of diabetic retinopathy. PloS one 2014 9(5) 24788674
Abstract:
Hyperglycemia is the primary cause of the majority of diabetes complications, including diabetic retinopathy (DR). Hyperglycemic conditions have a detrimental effect on many tissues and cell types, especially the retinal vascular cells including early loss of pericytes (PC). However, the mechanisms behind this selective sensitivity of retinal PC to hyperglycemia are undefined. The O-linked β-N-acetylglucosamine (O-GlcNAc) modification is elevated under hyperglycemic condition, and thus, may present an important molecular modification impacting the hyperglycemia-driven complications of diabetes. We have recently demonstrated that the level of O-GlcNAc modification in response to high glucose is variable in various retinal vascular cells. Retinal PC responded with the highest increase in O-GlcNAc modification compared to retinal endothelial cells and astrocytes. Here we show that these differences translated into functional changes, with an increase in apoptosis of retinal PC, not just under high glucose but also under treatment with O-GlcNAc modification inducers, PUGNAc and Thiamet-G. To gain insight into the molecular mechanisms involved, we have used click-It chemistry and LC-MS analysis and identified 431 target proteins of O-GlcNAc modification in retinal PC using an alkynyl-modified GlcNAc analog (GlcNAlk). Among the O-GlcNAc target proteins identified here 115 of them were not previously reported to be target of O-GlcNAc modification. We have identified at least 34 of these proteins with important roles in various aspects of cell death processes. Our results indicated that increased O-GlcNAc modification of p53 was associated with an increase in its protein levels in retinal PC. Together our results suggest that post-translational O-GlcNAc modification of p53 and its increased levels may contribute to selective early loss of PC during diabetes. Thus, modulation of O-GlcNAc modification may provide a novel treatment strategy to prevent the initiation and progression of DR.
O-GlcNAc proteins:
UBP36, PYR1, RBM25, TRIPC, CAN2, PRDX4, AIP, GSTO1, X3CL1, DHX15, HNRH1, AT2A2, GPX4, TRI18, O88568, HA1W, LDHA, ANXA2, RIR1, HS90A, ANXA1, HS90B, TCPA, UMPS, H12, LEG1, DDX3L, TPIS, HB2I, FAS, TPM3, IMDH2, MCM3, PSB8, SYWC, PRDX1, DNLI1, CAP1, STAT3, PURA, TCPQ, H14, H11, NEDD4, CAPZB, RL36, HS74L, ADT1, MCM4, RAB7A, ADT2, KPYM, RL10A, ACTN4, EF2, RIPK2, SF3B6, PCBP1, ABCE1, 1433E, RS11, 1433Z, 1433T, TBA1A, EM55, HNRH2, ELAV1, TP53B, TCPB, ARF1, PSME2, TBB5, UBA1, CNN2, TGM3, INF2, GUAA, FUBP2, LRRF1, DDX17, SRC8, MYL6, SAMH1, KHDR1, IRGM1, SPB6, VDAC3, ASNS, LAP2A, PPM1G, PSN2, ZN638, FXR1, SERA, PZP, NPM, GPDM, PUR2, NOP58, TPM4, NEST, TNKS1, RS9, MBB1A, ATX2L, FLNB, SYAC, LSS, CKAP4, HEAT3, THOP1, AROS, TXNL1, SYEP, STAU2, AGO4, HMCS1, PNPT1, ANLN, MATR3, WIPI1, MYH9, PARN, AT1A1, FLNC, RAB14, SFXN3, IPYR2, SMC1B, TADBP, LRC59, NONO, GRPE1, RTN4, NU155, OGFR, MTAP, CYB5B, MPPB, GARS, HNRPM, TRIR, IPYR, EF1G, PUR6, RAI14, LIMA1, PALLD, TMOD3, DDX21, WDR12, CUL3, TRXR1, DREB, ZBP1, TOM40, DNJC7, IIGP1, DEST, ACOT9, KAD2, TEN1, VAPA, GBP2, P5CS, SAE2, SYVC, HNRPF
Species: Mus musculus
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Chuh KN, Zaro BW, Piller F, Piller V, Pratt MR. Changes in metabolic chemical reporter structure yield a selective probe of O-GlcNAc modification. Journal of the American Chemical Society 2014 136(35) 25153642
Abstract:
Metabolic chemical reporters (MCRs) of glycosylation are analogues of monosaccharides that contain bioorthogonal functionalities and enable the direct visualization and identification of glycoproteins from living cells. Each MCR was initially thought to report on specific types of glycosylation. We and others have demonstrated that several MCRs are metabolically transformed and enter multiple glycosylation pathways. Therefore, the development of selective MCRs remains a key unmet goal. We demonstrate here that 6-azido-6-deoxy-N-acetyl-glucosamine (6AzGlcNAc) is a specific MCR for O-GlcNAcylated proteins. Biochemical analysis and comparative proteomics with 6AzGlcNAc, N-azidoacetyl-glucosamine (GlcNAz), and N-azidoacetyl-galactosamine (GalNAz) revealed that 6AzGlcNAc exclusively labels intracellular proteins, while GlcNAz and GalNAz are incorporated into a combination of intracellular and extracellular/lumenal glycoproteins. Notably, 6AzGlcNAc cannot be biosynthetically transformed into the corresponding UDP sugar-donor by the canonical salvage-pathway that requires phosphorylation at the 6-hydroxyl. In vitro experiments showed that 6AzGlcNAc can bypass this roadblock through direct phosphorylation of its 1-hydroxyl by the enzyme phosphoacetylglucosamine mutase (AGM1). Taken together, 6AzGlcNAc enables the specific analysis of O-GlcNAcylated proteins, and these results suggest that specific MCRs for other types of glycosylation can be developed. Additionally, our data demonstrate that cells are equipped with a somewhat unappreciated metabolic flexibility with important implications for the biosynthesis of natural and unnatural carbohydrates.
O-GlcNAc proteins:
A1BN54, A2A4Z1, A2A6U3, A2AFJ1, A2AG83, A2AL12, A2AMW0, A2AMY5, LAS1L, B1AU75, OTUD4, B7FAU9, B7ZP47, D3YUC9, D3YVJ7, SAFB1, D3Z4W3, E9PVC5, E9PZM7, E9Q066, E9Q2X6, E9Q310, E9Q5L7, E9Q7M2, E9Q986, F6T2Z7, G3UZ44, G3UZI2, G3X8Q0, G3X8Y3, G3X928, G3X972, G3X9V0, G5E8E1, H3BKK2, J3JS94, CAN2, DPYL2, AIP, HDAC1, MP2K3, GSH0, DHX15, ZW10, AKAP2, SLK, NMT1, E41L2, SRPK1, PARG, SPD2A, LDHA, ANXA2, RIR1, ANXA1, LMNB1, LEG1, G3P, TPIS, COF1, FAS, CBX3, BCAT1, MCM3, MAP4, FKBP4, HMGB2, AIMP1, MP2K1, SYWC, RANG, UBP4, PTN11, RAB5C, DNLI1, CAP1, STAT3, EPS15, PURA, MSH2, ALD2, PURA2, NEDD4, GFPT1, PCY1A, ICAL, HDGF, UBP10, ACTN4, EF2, TB182, SF3B6, PCBP1, PSME3, PFD3, HNRPK, MTPN, DNJA1, SUMO1, IF5A1, UB2L3, 1433T, HDAC2, ELAV1, 4EBP2, PYRG1, TCPB, BOP1, DAB2, XDH, UBA1, LARP7, CNN2, PP4R2, PSA, Q3TFP0, GUAA, METK2, FA98A, Q3TT92, UAP1L, NOL9, FUBP2, Q3U4W8, YRDC, NOL8, COBL1, CSTOS, LRRF1, Q3V3Y9, DDX17, MDC1, TENS3, Q5UE59, SRC8, SAMH1, KHDR1, SPB6, CAPR1, PAPS1, ASNS, LAP2B, LAP2A, PPM1G, CDC37, FXR1, HS105, PCBP2, KPCI, DDX3X, TSN, DBNL, CYTB, ZYX, RALY, SQSTM, TPP2, PUR2, PEAK1, NOP58, TPM4, LTV1, ZC11A, Q6P5B5, SMHD1, GGA2, TXLNA, JUPI2, UBE2O, LARP1, 2AAA, MTCH2, DEK, MBB1A, ATX2L, OTUB1, MAP6, AFTIN, FLNB, PI42B, ZN598, SAFB2, GRWD1, CPPED, LPP, PEF1, IF4B, SYAC, RUFY1, PRUN1, CTF18, AHSA1, RCC2, IPO5, CKAP4, PPR18, HEAT3, SRRM2, HAT1, MAP1S, TLK1, CND2, THOP1, SEP11, TBL3, SEP10, UBA6, SYEP, GNL3, PDLI5, HMCS1, PKHO2, NEK9, ANLN, MATR3, CBR3, MEPCE, ERF3A, SPART, TDIF2, MCMBP, UBP15, MAVS, Q8VCQ8, PSMD2, FLNC, CPIN1, ACLY, MK67I, RINI, PUS7, CSDE1, DUS3L, KCC1A, TTC1, TADBP, RIN1, NONO, RRAGC, SERB, UBQL4, OGFR, NPM3, GLOD4, MTAP, CYB5B, PSMD9, CHSP1, OCAD1, RANB3, MFR1L, TBC15, CYBP, ZCHC8, GARS, CD37L, UB2V1, HNRPM, Q9D4G5, NOP56, IPYR, CNN3, KAP0, PLIN3, AKAP8, XRN2, MYPT1, PUR6, WDR4, SENP3, LIMA1, ANM1, NUP50, DDX20, IQGA1, MBNL1, ELOV1, DCLK1, BAG3, PPCE, CAF1A, LIMD1, DREB, TOM40, DEST, FOXO1, NFKB2, PDC6I, COR1C, TAGL2, CARM1, MTNB, GBP2, P5CS, EIF3G, SAE2, USO1, HNRPF, KEAP1
Species: Mus musculus
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Trinidad JC, Barkan DT, Gulledge BF, Thalhammer A, Sali A, Schoepfer R, Burlingame AL. Global identification and characterization of both O-GlcNAcylation and phosphorylation at the murine synapse. Molecular & cellular proteomics : MCP 2012 11(8) 22645316
Abstract:
O-linked N-acetylglucosamine (O-GlcNAc) is a dynamic, reversible monosaccharide modifier of serine and threonine residues on intracellular protein domains. Crosstalk between O-GlcNAcylation and phosphorylation has been hypothesized. Here, we identified over 1750 and 16,500 sites of O-GlcNAcylation and phosphorylation from murine synaptosomes, respectively. In total, 135 (7%) of all O-GlcNAcylation sites were also found to be sites of phosphorylation. Although many proteins were extensively phosphorylated and minimally O-GlcNAcylated, proteins found to be extensively O-GlcNAcylated were almost always phosphorylated to a similar or greater extent, indicating the O-GlcNAcylation system is specifically targeting a subset of the proteome that is also phosphorylated. Both PTMs usually occur on disordered regions of protein structure, within which, the location of O-GlcNAcylation and phosphorylation is virtually random with respect to each other, suggesting that negative crosstalk at the structural level is not a common phenomenon. As a class, protein kinases are found to be more extensively O-GlcNAcylated than proteins in general, indicating the potential for crosstalk of phosphorylation with O-GlcNAcylation via regulation of enzymatic activity.
O-GlcNAc proteins:
A0JNY3, A2A653, A2A654, TANC2, ZEP3, MA7D2, CKAP5, CAMP1, LZTS3, A2AJ19, AJM1, MA7D1, A2ALK6, RPGP1, UBR4, A2AP92, SKT, ANR63, A2ATK9, A2AUD5, A2BI30, A6H6J9, A6MDD2, A8DUV1, B1AQX6, B1AR09, GRIK3, B1ATI9, B1AWT3, NHSL2, FRS1L, UBP24, DLGP4, B2RQ57, B2RQ80, PYR1, B2RQL0, B2RQQ5, GNAI1, B2RUE8, OTU7B, B2RWX1, B6ZHC4, B6ZHC5, B7ZCA7, B7ZMP8, B7ZNA4, B7ZNF6, B7ZWM6, B9EHE8, CTTB2, B9EKL9, PTPRZ, D1FNM8, D3YU59, D3YWX2, DGKH, D3YXR8, PGBD5, SHAN1, D3Z0V7, D3Z2J5, D9HP81, E0CYT1, E9PUA3, E9PUC4, DGKD, E9PUR0, E9PV14, E9PV26, KI67, E9PWL1, E9PWM3, E9PY55, E9PZP8, E9Q1M1, E9Q2B2, E9Q3D6, E9Q3G8, E9Q3M9, E9Q4N6, E9Q616, E9Q6T8, E9Q6Y8, NUMA1, E9Q828, E9Q9I2, E9Q9J6, E9QA16, E9QAP7, E9QAR5, SC16A, E9QJU8, E9QMJ1, SYGP1, RFIP2, HXK2, CAN2, SC22B, DPYL2, STXB1, TCOF, DCTN1, GLU2B, EF2K, PRDX4, AIP, NUMBL, GSTO1, GSH0, M3K5, PSMD4, DHX15, NPC1, BMPR2, VIAAT, BCAT2, CTND2, PITM1, CSK22, REPS1, ACK1, SLK, CAC1B, PGRC1, IMPA1, SYUA, AKA7A, STRN, RL35A, AT2A2, PGAM2, ATX2, NMT1, E41L2, GPX4, EMC8, DHB12, HCN4, KDM6A, ZN326, SORL, GRPE2, KLC1, ZFR, O88568, HCN2, HCN1, BSN, TOM1, RPP30, DNJB5, COX1, HA1D, HBA, K2C1, MBP, ALDOA, PGFRB, LDHA, G6PI, ENPP1, NEUM, ANXA2, RIR1, HS90A, EGR1, MDHM, KCC4, NFL, NFM, GNAI2, PDIA1, NUCL, CADH1, RC3H2, LRC4B, IGS11, DERPC, UBB, IFI5B, IFI4, ANXA1, EF1A1, H2B1F, PARP1, HS90B, DMD, KCC2A, TCPA, A4, COX5A, GELS, UMPS,