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O-deGlcNAcylation is required for <i>Entamoeba histolytica</i>-induced HepG2 cell death
Lee, Young Ah,Min, Arim,Shin, Myeong Heon Elsevier 2018 Microbial pathogenesis Vol.123 No.-
<P><B>Abstract</B></P> <P> <I>Entamoeba histolytica</I> is an enteric tissue-invading protozoan parasite that causes amoebic colitis and occasionally liver abscess in humans. <I>E. histolytica</I> can induce host-cell apoptosis by initiating various intracellular signaling mechanisms closely associated with tissue pathogenesis and parasitic immune evasion. O-GlcNAcylation, similar to phosphorylation, is involved in various cell-signaling processes, including apoptosis and proliferation, with O-GlcNAc addition and removal regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. However, whether O-GlcNAc alterations in host cells affect <I>E. histolytica</I>-induced cell death and which signal molecules participate in <I>E. histolytica</I>-induced deglycosylation remain unknown. In this study, co-incubation of HepG2 cells with <I>E. histolytica</I> increased DNA fragmentation and LDH release as compared with control cells. Additionally, Gal-lectin-mediated amoebic adherence of live trophozoites to HepG2 cells decreased O-GlcNAcylated protein levels within 5 min. We also observed a rapid decrease in cellular OGT protein level, but not OGA, in HepG2 cells in a contact-dependent manner. Furthermore, HepG2 pretreatment with OGA inhibitors or OGA siRNA prevented <I>E. histolytica</I>-induced O-deGlcNAcylation, DNA fragmentation, and LDH release. Our results suggested that <I>E. histolytica</I>-induced O-deGlcNAcylation in HepG2 cells was an important process required for hepatocyte cell death induced by <I>E. histolytica</I> adherence.</P> <P><B>Highlights</B></P> <P> <UL> <LI> <I>Entamoeba histolytica</I> remarkably induces cell death in HepG2 cells. </LI> <LI> O-GlcNAcylated proteins were rapidly and dramatically reduced in Entamoeba-treated HepG2 cells in a contact-dependent manner. </LI> <LI> Alteration of OGT/OGA expression with OGA inhibitor reduces <I>E. histolytica</I>-induced O-deGlcNAcylation in HepG2 cells. </LI> <LI> Inhibition of OGA activity reduces <I>Entamoeba</I>-induced host cell death in HepG2 cells. </LI> </UL> </P>
Min, Arim,Lee, Young Ah,Kim, Kyeong Ah,El-Benna, Jamel,Shin, Myeong Heon American Society for Microbiology 2017 Infection and immunity Vol.85 No.1
<P>Trichomonas vaginalis is a sexually transmitted parasite that causes vaginitis in women and itself secretes lipid mediator leukotriene B-4 (LTB4). Mast cells are important effector cells of tissue inflammation during infection with parasites. Membrane-bridging SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complexes are critical for fusion during exocytosis. Although T. vaginalis-derived secretory products (TvSP) have been shown to induce exocytosis in mast cells, information regarding the signaling mechanisms between mast cell activation and TvSP is limited. In this study, we found that SNAP23-dependent surface trafficking of LTB4 receptor 1 (BLT1) is required for nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2)-mediated exocytotic degranulation of mast cells induced by TvSP. First, stimulation with TvSP induced exocytotic degranulation and reactive oxygen species (ROS) generation in HMC-1 cells. Next, TvSP-induced ROS generation and exocytosis were strongly inhibited by transfection of BLT1 small interfering RNA (siRNA). TvSP induced trafficking of BLT1 from the cytosol to the plasma membrane. We also found that knockdown of SNAP23 abrogated TvSPinduced ROS generation, exocytosis, and surface trafficking of BLT1 in HMC-1 cells. By coimmunoprecipitation, there was a physical interaction between BLT1 and SNAP23 in TvSP-stimulated HMC-1 cells. Taken together, our results suggest that SNAP23-dependent surface trafficking of BLT1 is essential for exocytosis in human mast cells induced by T. vaginalis-secreted LTB4. Our data collectively demonstrate a novel regulatory mechanism for SNAP23-dependent mast cell activation of T. vaginalis-secreted LTB4 involving surface trafficking of BLT1. These results can help to explain how the cross talk mechanism between parasite and host can govern deliberately tissue inflammatory responses.</P>
Arim Min,Young Hee Nam,Young-Ah Lee,Kyoung-Ju Song,Myeong Heon Shin 한국당과학회 2012 한국당과학회 학술대회 Vol.2012 No.1
Degranulation in human mast cells contributes to provocation of allergic inflammation and innate immunity to parasites. Trichomonas vaginalis is transmitted by sexual intercourse and causes the acute and chronic allergic inflammation. Although a recent report has shown that mast cells are degranulated in response to T. vaginalis-derived secretory products (TvSP), detailed signaling mechanisms of TvSP- induced mast cell degranulation are not fully understood. We report that N-glycosylation of NOX2 play an important role in surface trafficking of NOX2, which can regulate ROS-dependent degranulation in TvSP- stimulated human mast cells. Stimulation with TvSPinduced NOX2 activation such as p47phox phosphorylation and NOX2 glycosylation, production of intracellular ROS, and release of granular proteins such as histamine and -hexosaminidase via BLT1. Inhibition of ROS generation with NOX2 inhibitors also reduced TvSP-triggered degranulation. Moreover, TvSP promoted trafficking of intracellular NOX2 to the cell surface in a BLT1-dependent manner. Such BLT1-mediated surface migration of NOX2 was dependent upon N-glycosyation status of NOX2. Inhibiting N-glycosylation of NOX2 by N-glycosylation inhibitor tunicamycin reduced surface trafficking of NOX2, ROS generation, and degranulation induced by TvSP. PKC inhibitor prevented TvSP-triggered glycosylation of NOX2, its surface trafficking, ROS generation, degranulation. Finally, disruption of lipid rafts with M □CD prevented glycosylation-dependent surface trafficking of NOX2, ROS generation, and degranulation. These results suggest that PKC-mediated N- glycosylation regulates its trafficking of NOX2 to the lipid rafts, which is required for ROS-dependent degranulation in mast cells induced by T. vaginalis-derived secretory products.
Trichomonas vaginalis-аар өдөөгдсөн шигүү мөхлөгт эсийн идэвхжилд MAP Kиназа сигналын үүрэг
Giimaa Narantsogt,Arim Min,Young Hee Nam,Temuulen Dorjsuren,Gurbadam Agvaandaram,Myeong Heon Shin 동중앙아시아경상학회 2015 한몽경상학회 학술대회 Vol.2015 No.04
Trichomonas vaginalis is a flagellated protozoan parasite that causes vaginitis and cervicitis in women and asymptomatic urethritis and prostatitis in men, respectively. Mast cells have been reported to be predominant in the vaginal smears and vaginal walls of patients infected with T. vaginalis. Mitogenactivated protein kinase (MAPK) activated by various stimuli also regulate the transcriptional activity of various cytokine genes in the mast cells. Because of their essential role in intracellular signaling network, also appropriate targets for pharmacological treatment of inflammatory disorders. In this study, we investigated whether MAPK were involved ROS generation and exocytotic degranulation in HMC-1 induced by T. vaginalis-derived secretory products (TvSP). We first examined that TvSP could induce activation of MAPK and NADPH oxidase in HMC-1 cells. Stimulation with TvSP induced phosphorylation of MAPK and p47phox in HMC-1 cells. Phosphorylation of p47phox is main source of ROS generation. Next, to determine involvement activation of MAPK in ROS generation and degranulation in HMC-1 cells induced by TvSP. ROS generation is required for exocytotic degranulation of mast cells induced by TvSP. Stimulation with TvSP induced phosphorylation of p47phox, ROS generation, surface up-regulation of CD63 in human mast cells. CD63 is a marker for exocytosis. Pretreatment with MAPK inhibitors strongly inhibited TvSP-induced ROS generation and exocytotic degranulation. Finally, our results suggest that TvSP could induce intracellular ROS generation and exocytotic degranulation in HMC-1 via MAPK signaling pathway.
Nam, Young Hee,Min, Arim,Kim, Seong Hoon,Lee, Young Ah,Kim, Kyeong Ah,Song, Kyoung-Ju,Shin, Myeong Heon Birkhäuser 2012 Inflammation research Vol.61 No.2
<P>Trichomonas vaginalis is a flagellated protozoan parasite that causes human trichomoniasis. Although T. vaginalis itself can secrete lipid mediator leukotriene (LT) B(4) leading to neutrophil activation, information regarding the signaling mechanism involved in neutrophil activation induced by T. vaginalis-secreted LTB(4) is limited. We investigated whether LTB(4) contained in the T. vaginalis-derived secretory products (TvSP) is closely involved in interleukin (IL)-8 production in human neutrophils via LTB(4) receptors BLT1 or BLT2.</P>
Young Hee Nam,Arim Min,Young-Ah Lee,Kyoung-Ju Song,Myeong Heon Shin 한국당과학회 2012 한국당과학회 학술대회 Vol.2012 No.1
Trichomonas vaginalis is a flagellated protozoan parasite causing vaginal trichomoniasis in women, and can secrete chemotactic lipid mediator LTB4 in their secretory products. However, signaling mechanisms of tissue inflammatory responses by infection with T. vaginalis are not fully understood. Recently, we have recently demonstrated that human mast cells and neutrophils are activated to produce chemokine IL-8 via LTB4 receptor BLT1 in response to T. vaginalis-derived secretory products (TvSP). Here, we report that O-glycosylation is important in BLT1-mediated IL-8 secretion in human mast cells (HMC-1 cell line) induced by TvSP. Incubation of HMC-1 cells with TvSP resulted in marked increase of O-GlcNacylated proteins and up-regulated IL-8 protein secretion. TvSP-induced IL-8 production and O-glycosylation in HMC-1 cells was inhibited by pretreatment with OGT inhibitor or OGT siRNA. Pretreatment of HMC-1 cells with BLT1 antagonist or BLT1 siRNA strongly abolished the stimulatory effects of TvSP on O-GlcNacylation and IL-8 production. Moreover, TvSP-induced phosphorylation of transcription factors NF-B and CREB for IL-8 production was reduced by pretreatment of HMC-1 cells with OGT inhibitor or OGT siRNA. These results suggest that BLT1-mediated O-glycosylation may play an important role in activation of transcription factors CREB and NF-B for IL-8 production in mast cells stimulated with TvSP, which can contribute to mast cell-mediated tissue inflammatory responses in T. vaginalis-infected lesion during human trichomoniasis.