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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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Lee BE, Kim HY, Kim HJ, Jeong H, Kim BG, Lee HE, Lee J, Kim HB, Lee SE, Yang YR, Yi EC, Hanover JA, Myung K, Suh PG, Kwon T, Kim JI. O-GlcNAcylation regulates dopamine neuron function, survival and degeneration in Parkinson disease. Brain : a journal of neurology 2020 143(12) 33300544
Abstract:
The dopamine system in the midbrain is essential for volitional movement, action selection, and reward-related learning. Despite its versatile roles, it contains only a small set of neurons in the brainstem. These dopamine neurons are especially susceptible to Parkinson's disease and prematurely degenerate in the course of disease progression, while the discovery of new therapeutic interventions has been disappointingly unsuccessful. Here, we show that O-GlcNAcylation, an essential post-translational modification in various types of cells, is critical for the physiological function and survival of dopamine neurons. Bidirectional modulation of O-GlcNAcylation importantly regulates dopamine neurons at the molecular, synaptic, cellular, and behavioural levels. Remarkably, genetic and pharmacological upregulation of O-GlcNAcylation mitigates neurodegeneration, synaptic impairments, and motor deficits in an animal model of Parkinson's disease. These findings provide insights into the functional importance of O-GlcNAcylation in the dopamine system, which may be utilized to protect dopamine neurons against Parkinson's disease pathology.
O-GlcNAc proteins:
BIG2, F1712, VIR, AJM1, RPGP1, UBR4, SCN1A, AGRIN, KALRN, STPG3, FXL16, TT23L, PTPRS, GRIK3, SCN2A, DLGP4, OSBL8, PTPRZ, PGBD5, GLSK, GCN1, CE350, PI4KA, RYR2, AGRF2, UBE4A, NRX2A, FRY, SYGP1, OTOGL, AT2B1, ANK3, CA2D1, DPYL2, STXB1, DCTN1, U5S1, GFRA2, GALT1, SEM4D, KIF3C, PLCA, PHB2, NCAM2, GRAK, PURB, IMA3, IMA7, PLD3, FOLH1, FKBP8, STX1A, PSDE, VIAAT, AP1B1, C1QBP, SYT3, HNRH1, SATT, CTND2, SDC4, AP3D1, RGS9, RGS7, CSK22, OX2G, AAKG1, CRYM, PROM1, CNTP1, ENTP2, BCKD, SNG1, NIPS1, NIPS2, SEPT7, AT2A2, DHX9, PI51C, PI42A, ITB5, GPX4, NPTX2, GNAZ, WDR1, S4A4, MTX2, CNTFR, ZFR, CSN3, HCN2, HCN1, CTBP1, BSN, MPP3, NOE1, CBPD, LGMN, COR1A, CYB, COX1, COX2, COX3, HPRT, ATP6, THY1, H3C, LAMC1, NU1M, NU2M, NU4M, NU5M, ATP8, GFAP, MBP, PRIO, ALDOA, KAPCA, AATM, TBA1B, TBA3, KIT, LDHA, G6PI, MDR1B, ENPP1, HS90A, ENPL, KCC4, NFL, NFM, RASN, PGK2, ITB1, PPBT, NUCL, PGK1, ACE, LRC4B, UBB, UBC, EF1A1, IF4A2,