Biology subjects

Park, J. G.

Publications and source records attributed to Park, J. G..

4 recordsLinked to original sources

bioRxiv2026

Symmetric Dimethylarginine Modification Drives Shared and Divergent Antigen Reactivity in Lupus

Systemic lupus erythematosus (SLE) features a broad array of autoantibodies against nuclear components, but the mechanisms driving this diversity are poorly understood. We investigated whether posttranslational arginine methylation creates common neo-epitopes that could unify this response. Using methylome-wide peptide arrays, we identified anti-symmetric dimethylarginine (SDMA) autoantibodies in 30-40% of SLE patients, with individualized reactivity fingerprints. A single anti-SDMA monoclonal antibody from MRL-lpr mice recognized multiple SDMA-modified antigens, and EBNA-1, an Epstein-Barr virus protein, bound SLE plasma in an SDMA-dependent manner, pointing to potential molecular mimicry. In a validation cohort of 201 patients, anti-SDMA titers correlated with SLEDAI-2K scores and inversely with C3/C4; seropositivity was overrepresented in younger patients, those with renal involvement, and anti-Sm-positive individuals. These results establish that anti-SDMA responses are common in SLE, target methylated arginine motifs across self and viral proteins, and serve as markers of active, complement-consuming disease. The patient-specific recognition of SDMA epitopes may underlie the serological heterogeneity that defines SLE.

biochemistry↗

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↗

bioRxiv2018

Multifunctional CRISPR/Cas9 with engineered immunosilenced human T cell epitopes

The application of Cas9 for genetic and epigenetic therapies in humans raises concerns over immunogenicity of this foreign protein. We report pre-existing human CD8+ T cell immunity to Streptococcus pyogenes Cas9 in the majority of healthy individuals screened. In a proof-of-principle study, we demonstrate that Cas9 protein can be modified to eliminate immunodominant epitopes through targeted mutation while preserving its function and specificity.

immunology↗