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Zhang Z, Huang Z, Awad M, Elsalanty M, Cray J, Ball LE, Maynard JC, Burlingame AL, Zeng H, Mansky KC, Ruan HB. O-GlcNAc glycosylation orchestrates fate decision and niche function of bone marrow stromal progenitors. eLife 2023 12 36861967
Abstract:
In mammals, interactions between the bone marrow (BM) stroma and hematopoietic progenitors contribute to bone-BM homeostasis. Perinatal bone growth and ossification provide a microenvironment for the transition to definitive hematopoiesis; however, mechanisms and interactions orchestrating the development of skeletal and hematopoietic systems remain largely unknown. Here, we establish intracellular O-linked β-N-acetylglucosamine (O-GlcNAc) modification as a posttranslational switch that dictates the differentiation fate and niche function of early BM stromal cells (BMSCs). By modifying and activating RUNX2, O-GlcNAcylation promotes osteogenic differentiation of BMSCs and stromal IL-7 expression to support lymphopoiesis. In contrast, C/EBPβ-dependent marrow adipogenesis and expression of myelopoietic stem cell factor (SCF) is inhibited by O-GlcNAcylation. Ablating O-GlcNAc transferase (OGT) in BMSCs leads to impaired bone formation, increased marrow adiposity, as well as defective B-cell lymphopoiesis and myeloid overproduction in mice. Thus, the balance of osteogenic and adipogenic differentiation of BMSCs is determined by reciprocal O-GlcNAc regulation of transcription factors, which simultaneously shapes the hematopoietic niche.
O-GlcNAc proteins:
RUNX2
Species: Homo sapiens
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Zhao M, Ren K, Xiong X, Xin Y, Zou Y, Maynard JC, Kim A, Battist AP, Koneripalli N, Wang Y, Chen Q, Xin R, Yang C, Huang R, Yu J, Huang Z, Zhang Z, Wang H, Wang D, Xiao Y, Salgado OC, Jarjour NN, Hogquist KA, Revelo XS, Burlingame AL, Gao X, von Moltke J, Lin Z, Ruan HB. Epithelial STAT6 O-GlcNAcylation drives a concerted anti-helminth alarmin response dependent on tuft cell hyperplasia and Gasdermin C. Immunity 2022 55(4) 35385697
Abstract:
The epithelium is an integral component of mucosal barrier and host immunity. Following helminth infection, the intestinal epithelial cells secrete "alarmin" cytokines, such as interleukin-25 (IL-25) and IL-33, to initiate the type 2 immune responses for helminth expulsion and tolerance. However, it is unknown how helminth infection and the resulting cytokine milieu drive epithelial remodeling and orchestrate alarmin secretion. Here, we report that epithelial O-linked N-Acetylglucosamine (O-GlcNAc) protein modification was induced upon helminth infections. By modifying and activating the transcription factor STAT6, O-GlcNAc transferase promoted the transcription of lineage-defining Pou2f3 in tuft cell differentiation and IL-25 production. Meanwhile, STAT6 O-GlcNAcylation activated the expression of Gsdmc family genes. The membrane pore formed by GSDMC facilitated the unconventional secretion of IL-33. GSDMC-mediated IL-33 secretion was indispensable for effective anti-helminth immunity and contributed to induced intestinal inflammation. Protein O-GlcNAcylation can be harnessed for future treatment of type 2 inflammation-associated human diseases.
O-GlcNAc proteins:
STAT6
Species: Mus musculus
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Bi Y, Deng Z, Ni W, Shrestha R, Savage D, Hartwig T, Patil S, Hong SH, Zhang Z, Oses-Prieto JA, Li KH, Quail PH, Burlingame AL, Xu SL, Wang ZY. Arabidopsis ACINUS is O-glycosylated and regulates transcription and alternative splicing of regulators of reproductive transitions. Nature communications 2021 12(1) 33574257
Abstract:
O-GlcNAc modification plays important roles in metabolic regulation of cellular status. Two homologs of O-GlcNAc transferase, SECRET AGENT (SEC) and SPINDLY (SPY), which have O-GlcNAc and O-fucosyl transferase activities, respectively, are essential in Arabidopsis but have largely unknown cellular targets. Here we show that AtACINUS is O-GlcNAcylated and O-fucosylated and mediates regulation of transcription, alternative splicing (AS), and developmental transitions. Knocking-out both AtACINUS and its distant paralog AtPININ causes severe growth defects including dwarfism, delayed seed germination and flowering, and abscisic acid (ABA) hypersensitivity. Transcriptomic and protein-DNA/RNA interaction analyses demonstrate that AtACINUS represses transcription of the flowering repressor FLC and mediates AS of ABH1 and HAB1, two negative regulators of ABA signaling. Proteomic analyses show AtACINUS's O-GlcNAcylation, O-fucosylation, and association with splicing factors, chromatin remodelers, and transcriptional regulators. Some AtACINUS/AtPININ-dependent AS events are altered in the sec and spy mutants, demonstrating a function of O-glycosylation in regulating alternative RNA splicing.
O-GlcNAc proteins:
A0A384LHA9
Species: Arabidopsis thaliana
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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
Species: Rattus norvegicus, Mus musculus
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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, SCY2B, 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
Species: Arabidopsis thaliana
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Myers SA, Peddada S, Chatterjee N, Friedrich T, Tomoda K, Krings G, Thomas S, Maynard J, Broeker M, Thomson M, Pollard K, Yamanaka S, Burlingame AL, Panning B. SOX2 O-GlcNAcylation alters its protein-protein interactions and genomic occupancy to modulate gene expression in pluripotent cells. eLife 2016 5 26949256
Abstract:
The transcription factor SOX2 is central in establishing and maintaining pluripotency. The processes that modulate SOX2 activity to promote pluripotency are not well understood. Here, we show SOX2 is O-GlcNAc modified in its transactivation domain during reprogramming and in mouse embryonic stem cells (mESCs). Upon induction of differentiation SOX2 O-GlcNAcylation at serine 248 is decreased. Replacing wild type with an O-GlcNAc-deficient SOX2 (S248A) increases reprogramming efficiency. ESCs with O-GlcNAc-deficient SOX2 exhibit alterations in gene expression. This change correlates with altered protein-protein interactions and genomic occupancy of the O-GlcNAc-deficient SOX2 compared to wild type. In addition, SOX2 O-GlcNAcylation impairs the SOX2-PARP1 interaction, which has been shown to regulate ESC self-renewal. These findings show that SOX2 activity is modulated by O-GlcNAc, and provide a novel regulatory mechanism for this crucial pluripotency transcription factor.
O-GlcNAc proteins:
SOX2
Species: Mus musculus
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Lewis BA, Burlingame AL, Myers SA. Human RNA Polymerase II Promoter Recruitment in Vitro Is Regulated by O-Linked N-Acetylglucosaminyltransferase (OGT). The Journal of biological chemistry 2016 291(27) 27129214
Abstract:
Although the O-linked N-acetylglucosamine (O-GlcNAc) modification of the RNA polymerase II C-terminal domain was described 20 years ago, the function of this RNA polymerase II (pol II) species is not known. We show here that an O-GlcNAcylated pol II species (pol IIγ) exists on promoters in vitro Inhibition of O-GlcNAc-transferase activity and O-GlcNAcylation prevents pol II entry into the promoter, and O-GlcNAc removal from pol II is an ATP-dependent step during initiation. These data indicate that O-GlcNAc-transferase activity is essential for RNA pol II promoter recruitment and that pol II goes through a cycling of O-GlcNAcylation at the promoter. Mass spectrometry shows that serine residues 2 and 5 of the pol II C-terminal domain are O-GlcNAcylated, suggesting an overlap with the transcription factor IIH (TFIIH)-dependent serine 5 phosphorylation events during initiation and P-TEFb (positive transcriptional elongation factor b) events during elongation. These data provide unexpected and important insights into the role of a previously ill-defined species of RNA polymerase II in regulating transcription.
O-GlcNAc proteins:
PAPOG
Species: Homo sapiens
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Morris M, Knudsen GM, Maeda S, Trinidad JC, Ioanoviciu A, Burlingame AL, Mucke L. Tau post-translational modifications in wild-type and human amyloid precursor protein transgenic mice. Nature neuroscience 2015 18(8) 26192747
Abstract:
The microtubule-associated protein tau has been implicated in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders. Reducing tau levels ameliorates AD-related synaptic, network, and behavioral abnormalities in transgenic mice expressing human amyloid precursor protein (hAPP). We used mass spectrometry to characterize the post-translational modification of endogenous tau isolated from wild-type and hAPP mice. We identified seven types of tau modifications at 63 sites in wild-type mice. Wild-type and hAPP mice had similar modifications, supporting the hypothesis that neuronal dysfunction in hAPP mice is enabled by physiological forms of tau. Our findings provide clear evidence for acetylation and ubiquitination of the same lysine residues; some sites were also targeted by lysine methylation. Our findings refute the hypothesis of extensive O-linked N-acetylglucosamine (O-GlcNAc) modification of endogenous tau. The complex post-translational modification of physiological tau suggests that tau is regulated by diverse mechanisms.
O-GlcNAc proteins:
KANL3, PTGDS, CTND2, RNF13, SYUA, CRIPT, BSN, THY1, CATB, TAU, AT1B2, CATD, STMN1, TB182, NACAM,