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Gonzalez-Rellan MJ, Parracho T, Heras V, Rodriguez A, Fondevila MF, Novoa E, Lima N, Varela-Rey M, Senra A, Chantada-Vazquez MDP, Ameneiro C, Bernardo G, Fernandez-Ramos D, Lopitz-Otsoa F, Bilbao J, Guallar D, Fidalgo M, Bravo S, Dieguez C, Martinez-Chantar ML, Millet O, Mato JM, Schwaninger M, Prevot V, Crespo J, Frühbeck G, Iruzubieta P, Nogueiras R. Hepatocyte-specific O-GlcNAc transferase downregulation ameliorates nonalcoholic steatohepatitis by improving mitochondrial function. Molecular metabolism 2023 75 37453647
Abstract:
O-GlcNAcylation is a post-translational modification that directly couples the processes of nutrient sensing, metabolism, and signal transduction, affecting protein function and localization, since the O-linked N-acetylglucosamine moiety comes directly from the metabolism of glucose, lipids, and amino acids. The addition and removal of O-GlcNAc of target proteins are mediated by two highly conserved enzymes: O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) and O-GlcNAcase (OGA), respectively. Deregulation of O-GlcNAcylation has been reported to be associated with various human diseases such as cancer, diabetes, and cardiovascular diseases. The contribution of deregulated O-GlcNAcylation to the progression and pathogenesis of NAFLD remains intriguing, and a better understanding of its roles in this pathophysiological context is required to uncover novel avenues for therapeutic intervention. By using a translational approach, our aim is to describe the role of OGT and O-GlcNAcylation in the pathogenesis of NAFLD.
O-GlcNAc proteins:
DJC25, TITIN, FIBA, AOXC, LEG9, CLCA, MTP, MYH11, NTCP, PRDX6, DLDH, HCD2, GLU2B, PRDX4, RL21, GSH0, HGD, AMACR, PHB2, DOPD, PSMD4, SRSF5, PAHX, AGT1, S27A2, BHMT1, ANXA3, AP1B1, CP4AE, TIM44, CALU, AL1A7, OST48, PGRC1, COPB2, NIPS1, RL35A, AT2A2, PSB5, DHX9, DPM1, EIF3D, EF1B, NMT1, UGDH, DHB12, WDR1, RDH7, ROA2, COMT, JAM1, IDHC, CP8B1, COPE, RBM3, CP1A1, ADH1, COX1, COX2, CO3, HVM14, IGKC, IGHG1, B2MG, HA1B, HBA, HBB1, K1C10, NU3M, ATP8, K2C1, ALDOA, AATC, AATM, K1C18, LDHA, G6PI, MAOX, ANXA2, ALBU, SPA3K, HS90A, PDIA4, ENPL, APOE, SODC, MDHM, PDIA1, NUCL, PGK1, FRIH, SODM, EF1A1, CATB, THIO, GSTM1, RRAS, H10, GPX1, HS90B, MUP2, K2C8, CP2D9, OTC, TCPA, FABPL, PDCD6, RL7A, MYH8, GPDA, RL27A, RS16, RL7, MDHC, RSSA, CALR, GTR2, HSPB1, PSMD3, ANXA6, RLA0, GLNA, NDKA, CAH3, LEG3, SRP14, PH4H, MUTA, ASSY, G3P, ENOA, PTBP1, AP2A2, SBP1, COX7C, UDB17, PPIA, TPIS, PTPRA, CATD, COF1, FAS, GSTP1, RL13A, COX5B, COX41, BIP, PRDX3, VIME, CP2A5, TPM3, VTDB, TGM2, EIF3A, MOV10, CATA, PPIB, CP2DA, LKHA4, AL1A1, CO8A2, RS2, URIC, TLN1, MOES, RADI, 3BHS3, CTNA1, U2AF2, DHE3, SYSC, MA2A1, RL3, PDIA3, PSB8, ACOHC, APEX1, ADHX, MUG1, GRN, DPP4, PABP1, FRIL1, OAT, VTNC, GSTA3, CTND1, ACBP, SCP2, LA, DRG1, CP2F2, HYES, RAB18, FAAA, FBRL, CALX, PRDX1, RL12, RL18, HEM6, NCPR, HMGCL, GRP75, CAP1, TKT, INMT, RL28, ACSL1, ECI1, SEPT2, STAT1, PURA, PXMP2, TCPQ, H14, PLIN2, ACADM, MYO1B, STT3A, QOR, ALDH2, AL3A2, CAZA2, GSHR, RL6, RL29, RLA1, RL5, RL13, RL36, ANXA5, LMNA, CBR1, T23O, ROA1, HPPD, ODBA, DHB8, DHI1, SAHH, GLYC, K2C6A, VATA, ACADV, PA2G4, RAB7A, ACADL, RL9, DHB2, DHB4, GSHB, ADT2, THTR, PON1, KPYM, RIDA, CPT2, ST1A1, ST2A1, RL10A, ODB2, KPYR, MOT1, CNBP, IDHP, HMCS2, ABCD3, RAB8A, ADK, ATPK, CX6B1, CYB5, ATPB, CP2AC, FUS, EF1D, ACTN4, TM9S2, EF2, GGLO, IF5, ARPC4, EIF3E, PCBP1, ACTB, CDC42, IF4A1, RS20, UBE2N, ARP2, ARF3, ABCE1, RL26, RL27, RL37A, S61A1, ARF4, GABT, HNRPK, 1433G, RRAS2, RS7, PP1B, PRS8, RS8, RS15A, 1433E, RS14, RS23, RS18, RS29, RS11, RS13, RS4X, RL18A, RL23A, RS6, H4, RAB1A, RAN, RL23, RS15, RS24, RS25, RS26, RS28, RS30, GBB2, RL30, CYC, RL31, RS3, RL32, RL8, YBOX1, PROF1, RS27A, RAC1, HSP7C, TCTP, DNJA1, CH60, 1433Z, IF5A1, RS17, RS10, PHB1, RL22, RACK1, ACTS, 1433T, TBA4A, TBB4B, TBA1C, 1433F, IMB1, EBP, NFIX, PEBP1, HNRH2, ELAV1, NHRF1, NACAM, DHB5, TCPB, TCPD, TCPE, TCPZ, TCPG, RL36A, AP2M1, RL19, ISC2A, KHK, RS3A, PSME2, ANXA4, MYL11, RS5, GSH1, FMO3, CPT1A, FUMH, CATC, LYPA1, G3BP1, FMO5, TBB5, RLA2, PRDX5, RET4, A1AT4, HNRL2, SC23A, NDKB, TERA, UBA1, PLAK, ATPA, PPA5, CP2E1, PYC, ATP5I, CLUS, ANXA7, ACADS, LG3BP, HSDL2, ML12B, METK2, K22E, AGT2, RMD3, MCCB, SC31A, IQGA2, S27A5, DDX17, OPA3, GLSL, ACBD5, COPD, A1CF, ODO1, MYL6, HNRPD, PSB6, GCDH, IRGM1, SPB6, STIP1, CAPR1, VDAC2, VDAC3, VDAC1, COQ8A, PRDX2, ARGI1, PLSL, ABCD2, HCDH, GPAT1, GDIB, HPT, DDX5, HS105, LASP1, NPM, NNTM, PCBP2, DDX3X, SSRD, SPR1A, NDUA4, CYTB, VAT1, SBP2, EST3A, UD11, SPRE, BTF3, RGN, CH10, UD16, DHSO, CP2CT, GSTT1, GPDM, CLH1, F120A, IF4G1, ODBB, ABCF1, LPPRC, SRSF1, RS9, RS27, RL10, RL35, IF2A, RS27L, H2B1C, KAT3, 2AAA, ATPMK, MIC27, 3HAO, S22AI, SND1, OSTC, MTCH2, NDUAC, HNRPQ, TBB2A, LDHD, ACTN1, GVIN1, MOGS, FA98B, COEA1, FLNB, ACD11, BDH, EFTU, LPP, ROA3, ALAT2, AL8A1, S2512, ECHM, CHDH, IPO5, TM214, SRP68, ECHA, SYNC, RL24, ASPH, FLNA, DHPR, AOFB, SSDH, ACOT4, UD2A3, THIM, ERF1, CPSM, NAKD2, MIC60, PARP9, THIC, S2545, G6PE, SYEP, LONM, NT8F2, DPYD, AL4A1, PDLI5, COPA, CP2DQ, EIF3B, ACSL5, TXTP, UD3A2, GALM, COQ9, SDHA, HACD3, MATR3, NDUS8, ALAT1, THIL, EIF3L, HNRPL, EPIPL, SGPL1, AL1L1, BPHL, EIF3C, CMBL, QCR9, H2AJ, SDHL, HUTU, AK1CD, TKFC, GYS2, THIKB, CGL, DHB13, ABHEB, EST1D, EST3B, ACSF2, MYH9, VIGLN, PSMD2, AT1A1, HNRPU, S25A3, SEC63, OASL1, SFPQ, TRAM1, CK054, ACLY, ACSM1, NDUS1, RINI, RMXL1, ATPG, DDX1, MGST1, CBR4, GCSP, NDUS2, EIF3H, KMO, SYYC, EST1F, BAAT, GCKR, DCXR, METK1, NADC, FTCD, GLYAT, TM205, ALDOB, ATLA3, ARLY, RPN1, NDUV1, GRHPR, PCCA, UGPA, FPPS, FADS1, TADBP, ETFD, THIKA, TRFE, PDIA5, SYDC, C1TC, MARC2, LRC59, PDIA6, ATAD3, SFXN2, ROAA, S14L2, THTM, STML2, SFXN1, GORS2, ECHB, ARP3, NONO, PLST, AASS, GLO2, ACON, DPP3, DHRS1, 3HIDH, IF2B, DHRS4, SARDH, NDUAA, ETFA, RTCB, PARK7, NDUS5, DNJA3, PCCB, MCCA, PECR, NUDT7, RTN4, AAAD, RRBP1, GDIR1, NDUA5, ATP5L, RL17, AMPL, DECR, MTAP, QCR8, NDUA2, SDHB, NDUB4, SAR1B, PCYOX, NDUB5, NDUB9, TXD17, TRAP1, AT5F1, ACO13, PPP6, SC61B, MTNA, RER1, 1433B, CYB5B, MAGT1, NDUA6, RL14, M2OM, TMM33, UCRI, VKOR1, OCAD1, ARPC2, MARC1, PUR9, DDAH1, ROA0, KYNU, CENPV, RL11, TECR, SERB1, QCR1, C560, RL15, GLYM, AL1B1, CISY, RS19, ODPB, HNRPM, LMAN1, PGM1, SYRC, CY1, SYTC, GAL3A, CNDP2, TMEDA, FKB11, ERP44, HYEP, HACD2, ATPD, PLCC, NDUV2, GHC1, IDH3A, MSRA, GLGB, ACAD8, PRPS1, SAPC2, IPYR, RL37, SOX, U2AF1, RL4, EF1G, ATPO, IAH1, QCR2, HUTI, CSAD, AL7A1, CP27A, AP2B1, RPN2, PGAM1, COASY, ECHP, KCY, M2GD, NDUA9, NDUS7, RT11, 6PGD, SSRG, EIF3F, NDUA8, PUR6, GSTK1, NB5R3, ASPDH, MTL26, NDUBA, NDUS3, HOGA1, RMD1, ETFB, ATP5H, KEG1, TMT1B, LACTB, RENT1, DHB11, MMSA, DPYS, ERAP1, VPS35, MVP, SET, RT29, PYGL, IVD, TMOD3, NIT2, COPB, AK1A1, CMLO1, PLS1, RL38, PXMP4, GNA1, AL9A1, CD2AP, STA10, TRXR1, RHOA, PSA6, K1C17, F16P1, HACL1, GNMT, S2513, CLIC4, VKGC, DIC, EIF3I, COPG1, TBL2, ACOX1, ESTD, DEST, TEBP, MPU1, SQOR, PSA1, TPSN, RUVB2, KAD3, HAOX1, PDC6I, PROD, SYFB, SUCA, PREB, ECI2, ENTP5, DECR2, TAGL2, ORNT1, PACN2, EHD1, MAAI, IF2G, BPNT1, AIFM1, DX39B, SYVC, ILF3, STRAP, HNRPC, PX11A, LETM1, SUCB2, SUCB1, PSA7, HNRPF, MCAT
Species: Mus musculus, Mus spicilegus
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Zaro BW, Batt AR, Chuh KN, Navarro MX, Pratt MR. The Small Molecule 2-Azido-2-deoxy-glucose Is a Metabolic Chemical Reporter of O-GlcNAc Modifications in Mammalian Cells, Revealing an Unexpected Promiscuity of O-GlcNAc Transferase. ACS chemical biology 2017 12(3) 28135057
Abstract:
Glycans can be directly labeled using unnatural monosaccharide analogs, termed metabolic chemical reporters (MCRs). These compounds enable the secondary visualization and identification of glycoproteins by taking advantage of bioorthogonal reactions. Most widely used MCRs have azides or alkynes at the 2-N-acetyl position but are not selective for one class of glycoprotein over others. To address this limitation, we are exploring additional MCRs that have bioorthogonal functionality at other positions. Here, we report the characterization of 2-azido-2-deoxy-glucose (2AzGlc). We find that 2AzGlc selectively labels intracellular O-GlcNAc modifications, which further supports a somewhat unexpected, structural flexibility in this pathway. In contrast to the endogenous modification N-acetyl-glucosamine (GlcNAc), we find that 2AzGlc is not dynamically removed from protein substrates and that treatment with higher concentrations of per-acetylated 2AzGlc is toxic to cells. Finally, we demonstrate that this toxicity is an inherent property of the small-molecule, as removal of the 6-acetyl-group renders the corresponding reporter nontoxic but still results in protein labeling.
O-GlcNAc proteins:
A2A5R8, A2A6U3, A2AF81, A2AG39, A2AIW9, A2AJ72, A2AJI1, A2AKV2, A2AL12, A2AMW0, A2AUR3, LAS1L, TRM1L, A5A4Y9, A6PWC3, B0QZF8, B1AU76, UPP, B7ZC19, B7ZP47, B8JJC1, D3YWF6, D3YWK1, D3YWS3, D3YYP4, E9PX53, E9Q066, I2BP2, E9Q4Q2, E9Q5L7, E9Q7W0, E9QP59, F8WGW3, G3UX26, G3UYZ0, G3UZ44, G3X972, H3BKW0, H7BWX9, GTPB1, AIP, ATOX1, HDAC1, GSH0, DHX15, IKBE, AKAP2, SLK, IMPCT, IF6, ACOT1, NMT1, DHB12, SRPK1, ZN326, KLC1, RPP30, IDHC, CASP8, GCR, TYSY, RIR1, S10AA, LEG1, G3P, TPIS, PRDX3, CBX3, TISD, CATA, IMDH2, NFKB1, MAP4, CEBPB, CDK4, FKBP4, HMGB2, KAP3, MP2K1, RANG, PTN11, FBRL, PTN12, FMR1, HMGCL, DYN1, CAP1, STAT1, STAT3, PURA, ALD2, SIPA1, PURA2, GSHR, FOSL2, FOSL1, GSTM5, PCY1A, VATA, HDGF, UBP10, RHOX5, HMGA2, CCHL, NUB1, FAF1, ZNRD2, TB182, PCBP1, ARL1, PFD3, TCTP, HMGB1, DYL1, UB2L3, HDAC2, ELAV1, 4EBP2, PYRG1, TCPB, SPTC2, PSME2, BOP1, WBP2, XDH, HMMR, E2AK2, CO6A1, FABP5, LARP7, CNN2, PP4R2, RM10, Q3TFP0, GUAA, FUBP2, TRADD, CTU2, Q3U4W8, SNX27, BABA1, EDC4</