Hong Dong

The Ohio State University

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Haitao Wen

The Ohio State University

Bao Zhao

The Ohio State University

Yu L. Lei

Qinghai University

Jianwen Chen

The Ohio State University

Cheng Xiang

National University of Singapore

Jing Wang

Hebei North University

Gang Xin

The Ohio State University

Jennifer D. Black

University of Nebraska Medical Center

Zihai Li

The Ohio State University

Junran Zhang

The Ohio State University

Cooperative Institutions

Amgen (United States)

The Ohio State University

Array BioPharma (United States)

Merck & Co., Inc., Rahway, NJ, USA (United States)

Toranomon Hospital

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

The Ohio State University Wexner Medical Center

Niigata University

Sichuan Agricultural University

Chinese Academy of Sciences

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O-GlcNAc transferase plays dual antiviral roles by integrating innate immunity and lipid metabolism

The Journal of Immunology (2024)

Hong Dong Chenxi Liang Jacob S. Yount Shan‐Lu Liu Haitao Wen

Abstract Challenge of host cells with viral pathogens induces robust metabolic reprogramming; however, whether viral component(s) is detected by metabolic enzyme remains completely unknown. Our previous study identified the O-GlcNAc transferase (OGT), an important glucose metabolic enzyme, as a crucial mediator of MAVS-dependent antiviral response. Here, by studying a mouse model with enzyme-inactive OGT, we demonstrate an enzyme-independent function of OGT in limiting influenza A virus (IAV) infection, in addition to its enzyme-dependent effect on MAVS. Biochemical studies reveal a critical antiviral effect of OGT binding with IAV genomic RNA via its N-terminal tetratricopeptide repeats-4 domain. Binding with viral RNA causes a robust translocation of nuclear OGT to cytosolic lipid droplets (LDs) and subsequently antagonizes LD accumulation via destabilizing perilipin 2. This LD-targeting effect of OGT limits IAV replication without altering MAVS signaling. Our findings reveal OGT as a multifaceted metabolic sensor by integrating MAVS-dependent innate immune signaling and lipid metabolism.

Transferase

10.4049/jimmunol.212.supp.0176.4285

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Diastereoselective Synthesis and Configuration‐Dependent Activity of (3‐Substituted‐cycloalkyl)glycine Pyrrolidides and Thiazolidides as Dipeptidyl Peptidase IV Inhibitors.

ChemInform (2004)

Wallace T. Ashton Hong Dong Rosemary M. Sisco George A. Doss Barbara Leiting

Abstract For Abstract see ChemInform Abstract in Full Text.

Dipeptidyl peptidase

10.1002/chin.200425243

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Effect of nebulized hypertonic saline solution for bronchiolitis in infant

Zhongguo jiceng yiyao (2017)

Shan-Pu Yang Hongyan Liu Yuechao Wu Ailin Lin Hong Dong

Objective To assess the efficacy and safety of nebulized hypertonic saline solution in infant with bronchiolitis. Methods From January 2014 to January 2016, 95 patients at 3-13 months old in our hospital who diagnosed as bronchiolitis were randomly divided into three groups.On the basis of conventional suit support treatment, the observation group A was given nebulized 3% hypertonic saline (n=32), the observation group B was given nebulized 3% hypertonic saline and salbutamol (n=32), and the control group C was given nebulized normal saline(0.9%) and salbutamol (n=31), this therapy was repeated every 6 hours until discharge.The Lowell score, clinical symptoms remission time, days of hospitalization and incidence rate of adverse reaction of the three groups were compared. Results After treatment, the symptoms and signs of the three groups were all improved.The Lowell scores were lower in the two observation groups compared to the control group C in 24, 48, 72 hours after treatment[(5.81±1.53)points and (5.85±1.37) points vs.(6.61±1.54) points, (4.75±1.34) points and (4.72±1.30) points vs.(5.52±1.29) points, (3.19±1.15) points and (3.22±1.16) points vs.(3.90±1.01) points, Z=-1.999, -2.241, -2.518 and -2.002, -2.335, -2.316, all P 0.05]. Children in three groups had no serious adverse events (all P>0.05). Conclusion Nebulized hypertonic saline in the treatment of bronchiolitis can relieve symptoms and signs, shorten the hospitalization time, and has less adverse reaction, it is worthy of clinical use. Key words: Bronchiolitis; Sodium chloride; Nebulize

Hypertonic saline

Acute Bronchiolitis

10.3760/cma.j.issn.1008-6706.2017.21.008

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Reviewer #1 (Public Review): Inhibition of O-GlcNAc transferase activates type I interferon-dependent antitumor immunity by bridging cGAS-STING pathway

Jianwen Chen Bao Zhao Tianliang Li Hong Dong Cheng Xiang

The O-GlcNAc transferase (OGT) is an essential enzyme that mediates protein O-GlcNAcylation, a unique form of posttranslational modification of many nuclear and cytosolic proteins. Recent studies observed increased OGT and O-GlcNAcylation levels in a broad range of human cancer tissues compared to adjacent normal tissues, indicating a universal effect of OGT in promoting tumorigenesis. Here, we show that OGT is essential for tumor growth in immunocompetent hosts by repressing the cyclic GMP-AMP synthase (cGAS)-dependent DNA sensing pathway. We found that deletion of OGT (Ogt−/−) caused a marked reduction in tumor growth in both syngeneic tumor models and a genetic colorectal cancer (CRC) model induced by mutation of the Apc gene (Apcmin). Pharmacological inhibition or genetic deletion of OGT induced a robust genomic instability (GIN), leading to cGAS-dependent production of the type I interferon (IFN-I) and IFN-stimulated genes (ISGs). As a result, deletion of Cgas or Sting from Ogt−/− cancer cells restored tumor growth, and this correlated with impaired CD8+ T cell-mediated antitumor immunity. Mechanistically, we found that OGT-dependent cleavage of host cell factor C1 (HCF-1) is required for the avoidance of GIN and IFN-I production in tumors. In summary, our results identify OGT-mediated genomic stability and activate cGAS-STING pathway as an important tumor cell-intrinsic mechanism to repress antitumor immunity.

Sting

10.7554/elife.94849.1.sa1

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Mitochondrial calcium uniporter promotes phagocytosis-dependent activation of the NLRP3 inflammasome

Proceedings of the National Academy of Sciences (2022)

Hong Dong Bao Zhao Jianwen Chen Zihao Liu Xinghui Li

Mitochondria, a highly metabolically active organelle, have been shown to play an essential role in regulating innate immune function. Mitochondrial Ca

ESCRT

10.1073/pnas.2123247119

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Author response: Inhibition of O-GlcNAc transferase activates type I interferon-dependent antitumor immunity by bridging cGAS-STING pathway

Jianwen Chen Bao Zhao Hong Dong Tianliang Li Cheng Xiang

Sting

10.7554/elife.94849.3.sa3

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Dipeptidyl peptidase IV inhibitors derived from β-aminoacylpiperidines bearing a fused thiazole, oxazole, isoxazole, or pyrazole

Bioorganic & Medicinal Chemistry Letters (2005)

Wallace T. Ashton Rosemary M. Sisco Hong Dong Kathryn A. Lyons Huaibing He

Thiazole

Oxazole

Isoxazole

Pyrazole

IC50

Dipeptidyl peptidase

10.1016/j.bmcl.2005.03.012

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Inhibition of O-GlcNAc transferase activates type I interferon-dependent antitumor immunity by bridging cGAS-STING pathway

Jianwen Chen Bao Zhao Hong Dong Tianliang Li Cheng Xiang

The O -GlcNAc transferase (OGT) is an essential enzyme that mediates protein O -GlcNAcylation, a unique form of posttranslational modification of many nuclear and cytosolic proteins. Recent studies observed increased OGT and O -GlcNAcylation levels in a broad range of human cancer tissues compared to adjacent normal tissues, indicating a universal effect of OGT in promoting tumorigenesis. Here, we show that OGT is essential for tumor growth in immunocompetent hosts by repressing the cyclic GMP-AMP synthase (cGAS)-dependent DNA sensing pathway. We found that deletion of OGT ( Ogt −/− ) caused a marked reduction in tumor growth in both syngeneic tumor models and a genetic colorectal cancer (CRC) model induced by mutation of the Apc gene ( Apc min ). Pharmacological inhibition or genetic deletion of OGT induced a robust genomic instability (GIN), leading to cGAS-dependent production of the type I interferon (IFN-I) and IFN-stimulated genes (ISGs). As a result, deletion of Cgas or Sting from Ogt −/− cancer cells restored tumor growth, and this correlated with impaired CD8 + T cell-mediated antitumor immunity. Mechanistically, we found that OGT-dependent cleavage of host cell factor C1 (HCF-1) is required for the avoidance of GIN and IFN-I production in tumors. In summary, our results identify OGT-mediated genomic stability and activate cGAS-STING pathway as an important tumor cell-intrinsic mechanism to repress antitumor immunity.

10.7554/elife.94849.2

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Aryl sulfones as novel Bradykinin B1 receptor antagonists for treatment of chronic pain

Bioorganic & Medicinal Chemistry Letters (2008)

Kaustav Biswas Toshihiro Aya Wenyuan Qian Tanya A.N. Peterkin Jian Jeffrey Chen

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Bradykinin receptor

10.1016/j.bmcl.2008.07.108

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Mitochondrial calcium uniporter positively regulates phagocytosis-dependent activation of NLRP3 inflammasome

The Journal of Immunology (2021)

Hong Dong Bao Zhao Haitao Wen

Abstract Mitochondria have been shown to play an essential role in the innate immune function and inflammatory response. Mitochondrial Ca2+ signaling, which is controlled by mitochondrial Ca2+ uniporter (MCU), is a fundamental mechanism regulating mitochondrial metabolism. Accumulative evidence suggests MCU-dependent mitochondrial Ca2+ signaling may bridge the metabolic reprogramming and regulation of immune cell function. However, the mechanism by which MCU regulates inflammation and its related disease remains elusive. Here we report a critical role of MCU in promoting phagocytosis-dependent activation of the NLRP3 inflammasome by dampening phagosome membrane repair. Myeloid deletion of MCU (McuΔmye) resulted in decreased caspase-1 cleavage and IL-1β maturation in response to the challenge with silica and alum, but not ATP and nigericin, in lipopolysaccharide (LPS)-primed macrophages. Stimulation with poly(dA:dT) or flagellin induced a similar IL-1β release between McuΔmye and wild-type (WT) macrophages. Mechanistically, we detected an enhanced phagosomal recruitment of ESCRT (endosomal sorting complex required for transport)-III complex in McuΔmye macrophages after silica or alum stimulation compared to similarly treated WT cells. ESCRT-III complex is known to be essential for repair of phagosomal membrane after damage, suggesting that deletion of MCU might lead to improved phagosomal membrane repair to limit NLRP3 inflammasome activation. Furthermore, McuΔmye mice showed attenuated inflammatory response and tissue damage in a chemically induced colitis model. In sum, our results identify a novel function and mechanism of MCU in regulating phagocytosis-dependent NLRP3 inflammatory response.

10.4049/jimmunol.206.supp.15.01

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