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White CW 3rd, Fan X, Maynard JC, Wheatley EG, Bieri G, Couthouis J, Burlingame AL, Villeda SA. Age-related loss of neural stem cell O-GlcNAc promotes a glial fate switch through STAT3 activation. Proceedings of the National Academy of Sciences of the United States of America 2020 117(36) 32848054
Abstract:
Increased neural stem cell (NSC) quiescence is a major determinant of age-related regenerative decline in the adult hippocampus. However, a coextensive model has been proposed in which division-coupled conversion of NSCs into differentiated astrocytes restrict the stem cell pool with age. Here we report that age-related loss of the posttranslational modification, O-linked β-N-acetylglucosamine (O-GlcNAc), in NSCs promotes a glial fate switch. We detect an age-dependent decrease in NSC O-GlcNAc levels coincident with decreased neurogenesis and increased gliogenesis in the mature hippocampus. Mimicking an age-related loss of NSC O-GlcNAcylation in young mice reduces neurogenesis, increases astrocyte differentiation, and impairs associated cognitive function. Using RNA-sequencing of primary NSCs following decreased O-GlcNAcylation, we detected changes in the STAT3 signaling pathway indicative of glial differentiation. Moreover, using O-GlcNAc-specific mass spectrometry analysis of the aging hippocampus, together with an in vitro site-directed mutagenesis approach, we identify loss of STAT3 O-GlcNAc at Threonine 717 as a driver of astrocyte differentiation. Our data identify the posttranslational modification, O-GlcNAc, as a key molecular regulator of regenerative decline underlying an age-related NSC fate switch.
O-GlcNAc proteins:
STAT3
Species: Mus musculus
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Liu B, Salgado OC, Singh S, Hippen KL, Maynard JC, Burlingame AL, Ball LE, Blazar BR, Farrar MA, Hogquist KA, Ruan HB. The lineage stability and suppressive program of regulatory T cells require protein O-GlcNAcylation. Nature communications 2019 10(1) 30664665
Abstract:
Regulatory T (Treg) cells control self-tolerance, inflammatory responses and tissue homeostasis. In mature Treg cells, continued expression of FOXP3 maintains lineage identity, while T cell receptor (TCR) signaling and interleukin-2 (IL-2)/STAT5 activation support the suppressive effector function of Treg cells, but how these regulators synergize to control Treg cell homeostasis and function remains unclear. Here we show that TCR-activated posttranslational modification by O-linked N-Acetylglucosamine (O-GlcNAc) stabilizes FOXP3 and activates STAT5, thus integrating these critical signaling pathways. O-GlcNAc-deficient Treg cells develop normally but display modestly reduced FOXP3 expression, strongly impaired lineage stability and effector function, and ultimately fatal autoimmunity in mice. Moreover, deficiency in protein O-GlcNAcylation attenuates IL-2/STAT5 signaling, while overexpression of a constitutively active form of STAT5 partially ameliorates Treg cell dysfunction and systemic inflammation in O-GlcNAc deficient mice. Collectively, our data demonstrate that protein O-GlcNAcylation is essential for lineage stability and effector function in Treg cells.
O-GlcNAc proteins:
FOXP3
Species: Mus musculus
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Kim S, Maynard JC, Strickland A, Burlingame AL, Milbrandt J. Schwann cell O-GlcNAcylation promotes peripheral nerve remyelination via attenuation of the AP-1 transcription factor JUN. Proceedings of the National Academy of Sciences of the United States of America 2018 115(31) 30012597
Abstract:
Schwann cells (SCs), the glia of the peripheral nervous system, play an essential role in nerve regeneration. Upon nerve injury, SCs are reprogrammed into unique "repair SCs," and these cells remove degenerating axons/myelin debris, promote axonal regrowth, and ultimately remyelinate regenerating axons. The AP-1 transcription factor JUN is promptly induced in SCs upon nerve injury and potently mediates this injury-induced SC plasticity; however, the regulation of these JUN-dependent SC injury responses is unclear. Previously, we produced mice with a SC-specific deletion of O-GlcNAc transferase (OGT). This enzyme catalyzes O-GlcNAcylation, a posttranslational modification that is influenced by the cellular metabolic state. Mice lacking OGT in SCs develop a progressive demyelinating peripheral neuropathy. Here, we investigated the nerve repair process in OGT-SCKO mutant mice and found that the remyelination of regenerating axons is severely impaired. Gene expression profiling of OGT-SCKO SCs revealed that the JUN-dependent SC injury program was elevated in the absence of injury and failed to shut down at the appropriate time after injury. This aberrant JUN activity results in abnormalities in repair SC function and redifferentiation and prevents the timely remyelination. This aberrant nerve injury response is normalized in OGT-SCKO mice with reduced Jun gene dosage in SCs. Mechanistically, OGT O-GlcNAcylates JUN at multiple sites, which then leads to an attenuation of AP-1 transcriptional activity. Together, these results highlight the metabolic oversight of the nerve injury response via the regulation of JUN activity by O-GlcNAcylation, a pathway that could be important in the neuropathy associated with diabetes and aging.
O-GlcNAc proteins:
JUN, JUN
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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, Q9C9H8, 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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