Biology subjects

Cho, J. Y.

Publications and source records attributed to Cho, J. Y..

5 recordsLinked to original sources

bioRxiv2022

Global loss of cellular m6A RNA methylation following infection with different SARS-CoV-2 variants

Host-viral interactions during SARS-CoV-2 infection are needed to understand COVID-19 pathogenesis and may help to guide the design of novel antiviral therapeutics. N6-methyladenosine modification (m6A), one of the most abundant cellular RNA modifications, regulates key processes in RNA metabolism during a stress response. Gene expression profiles observed post-infection with different SARS-CoV-2 variants show changes in the expression of genes related to RNA catabolism, including m6A readers and erasers. We found that infection with SARS-CoV-2 variants caused a loss of m6A in cellular RNAs, whereas m6A was detected abundantly in viral RNA. METTL3, the m6A methyltransferase, showed an unusual cytoplasmic localization post-infection. The B.1.351 variant had a less pronounced effect on METTL3 localization and loss of m6A than the B.1 and B.1.1.7 variants. We also observed a loss of m6A upon SARS-CoV-2 infection in air/liquid interface cultures of human airway epithelia, confirming that m6A loss is characteristic of SARS-CoV-2 infected cells. Further, transcripts with m6A modification were preferentially down-regulated post-infection. Inhibition of the export protein XPO1 resulted in the restoration of METTL3 localization, recovery of m6A on cellular RNA, and increased mRNA expression. Stress granule formation, which was compromised by SARS-CoV-2 infection, was restored by XPO1 inhibition and accompanied by a reduced viral infection in vitro. Together, our study elucidates how SARS-CoV-2 inhibits the stress response and perturbs cellular gene expression in an m6A-dependent manner.

molecular biology↗

bioRxiv2019

MyD88-Syk axis is a critical determinant for inflammatory response in macrophages

Inhibition of Syk or MyD88 decreased generation of reactive oxygen species (ROS)/reactive nitrogen species (RNS) and consequent ROS/RNS-induced phagocytic activity in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Syk inhibition downregulated expression of ROS/RNS-generating enzymes by inhibiting the nuclear factor-kappa B (NF-kappa?B) signaling pathway and phagocytic activity by suppressing suppressor of cytokine signaling 1 (SOCS1) via its nitration in the LPS-stimulated RAW264.7 cells. Inhibition of ROS/RNS generation suppressed SOCS1 nitration, leading to a decrease in the phagocytic activity. Syk was activated by the interaction with MyD88, and the tyrosine 58 residue (Y58) in the hemi-immunoreceptor tyrosine-based activation motif (ITAM) of MyD88 was critical for interaction and consequent activation of Syk in macrophages. Src activated MyD88 by phosphorylation at Y58 via the Src kinase domain. Moreover, LPS-induced formation of filamentous actin (F-actin) and Ras-related C3 botulinum toxin substrate 1 (Rac1) activation induced Src activation. Conclusivley, these results suggest that the MyD88-Syk axis plays a pivotal role in macrophage-mediated inflammatory responses by inducing ROS/RNS generation and phagocytic activity via activation of Src and its upstream stimulators, F-actin and Rac1.

immunology↗

bioRxiv2019

Metastatic function of METTL18 in breast cancer via actin methylation and Src

Recently, a SET domain containing 3 (SETD3) was identified as an actin histidine methyltransferase, functioning to control replication and pathogenesis in multiple mouse models for enterovirus infection as well as the regulation of smooth muscle contractility linked to primary dystocia. Here, in this study, we report another type of actin histidine methyltransferase, METTL18, that regulates the metastatic potential of breast cancer in human. Among methyltransferases, METTL18 was highly amplified in human breast cancer. In particular, poor prognosis was associated with high expression of METTL18 in HER2-negative breast cancer patients. This gene product was also found to be a critical component of metastatic responses. Loss of METTL18 expression significantly reduced metastatic responses of breast tumor cells both in vitro and in vivo. Mechanistically, it was observed that METTL18 increased actin polymerization, upregulated complex formation with HSP90AA1 and Src, enhanced the activity of an intermediate form of Src with tyrosine phosphorylation at both Y416 and Y527, and induced cellular metastatic responses, including morphological change, migration, and invasion of MDA-MB-231 cells in vitro and in mice. Methylated actin at His73 served as a critical site for interaction with HSP90AA1 and Src to activate p85/PI3K and STAT3. Our findings suggest that METTL18 plays critical roles in metastatic responses of HER2-negative breast cancer cells via actin polymerization and the generation of an intermediate form of Src.

cancer biology↗

bioRxiv2019

MEF2C hypofunction in neuronal and neuroimmune populations cooperate to produce MEF2C haploinsufficiency syndrome-like behaviors in mice

Microdeletions of the MEF2C gene are linked to a syndromic form of autism termed MEF2C haploinsufficiency syndrome (MCHS). Here, we show that MCHS-associated missense mutations cluster in the conserved DNA binding domain and disrupt MEF2C DNA binding. DNA binding-deficient global Mef2c heterozygous mice (Mef2c-Het) display numerous MCHS-like behaviors, including autism-related behaviors, as well as deficits in cortical excitatory synaptic transmission. We find that hundreds of genes are dysregulated in Mef2c-Het cortex, including significant enrichments of autism risk and excitatory neuron genes. In addition, we observe an enrichment of upregulated microglial genes, but not due to neuroinflammation in the Mef2c-Het cortex. Importantly, conditional Mef2c heterozygosity in forebrain excitatory neurons reproduces a subset of the Mef2c-Het phenotypes, while conditional Mef2c heterozygosity in microglia reproduces social deficits and repetitive behavior. Together our findings suggest that MEF2C regulates typical brain development and function through multiple cell types, including excitatory neuronal and neuroimmune populations.

neuroscience↗

bioRxiv2018

Generality and opponency of rostromedial tegmental (RMTg) roles in valence processing

The rostromedial tegmental nucleus (RMTg), a GABAergic afferent to midbrain dopamine (DA) neurons, has been hypothesized to encode aversive stimuli. However, this encoding pattern has only been demonstrated for a limited number of stimuli, and its influence on the ventral tegmental (VTA) responses to aversive stimuli is untested. Here, we found that RMTg neurons show average inhibitions to rewarding stimuli and excitations to aversive stimuli of greatly varying sensory modalities and timescales. Notably, negative valence-encoding neurons are particularly enriched in subpopulations projecting to the VTA versus other targets. Additionally, RMTg neurons also dynamically encode \"opponent\" changes in motivational states induced by removal of sustained stimuli. Finally, excitotoxic RMTg lesions impair conditioned place aversion to multiple aversive stimuli, and greatly reduce aversive stimulus-induced inhibitions in VTA neurons, particularly in putative DA-like neurons. Together, our findings indicate a broad RMTg role in encoding aversion and potentially driving DA responses and behavior.

neuroscience↗