Biology subjects

Shin, C. H.

Publications and source records attributed to Shin, C. H..

4 recordsLinked to original sources

bioRxiv2026

Zn2+ as a secondary messenger for exogenous redox potential sensed through Chemosensory Zinc-Binding (CZB) protein domains

Redox environments in nature are shaped by reactive oxygen species (ROS), oxygen availability, and metal ion chemistry, and exert profound effects on cell physiology and survival. While extensive work has characterized how cells resist oxidative damage, the mechanisms by which cells sense and navigate environmental redox conditions remain less well understood. Here, we identify a previously unrecognized and widespread mechanism of redox sensing in Salmonella enterica serovar Typhimurium mediated by the chemosensory zinc-binding (CZB) domain-containing receptor McpA. Using quantitative chemotaxis assays and live-cell imaging, we show that S. Typhimurium exhibits robust, concentration-dependent chemotaxis toward the neutrophil-derived oxidants HOCl and hydroperoxides, with attraction occurring at low, physiologically relevant concentrations below those that cause bactericidal effects, and this response requires McpA and its conserved zinc-binding cysteine. Whereas other Cys-Zn thiolate systems function through direct oxidation mechanisms, we find that the unique 3His,1Cys binding motif of CZBs responds to redox-dependent changes in Zn{superscript 2} speciation, whereby oxidizing conditions shift soluble, bioavailable Zn{superscript 2} into insoluble zinc precipitates. In this way, CZBs utilize the bioavailable Zn{superscript 2} pool as a secondary messenger of exogenous redox potential, and correspondingly, cells exhibit chemoattraction toward Zn{superscript 2}-depleted environments, including sources of ROS, but also toward oxygen-rich conditions that provide a metabolic growth advantage. The broad phylogenetic distribution of CZB domains is consistent with this Zn{superscript 2}-responsive mechanism being an ancient redox-sensing strategy, likely established early in bacterial evolution under changing planetary redox conditions and retained across diverse bacterial lineages. Significance StatementWe report a previously unknown mechanism of redox sensing that operates through changes in the bioavailability and speciation of Zn{superscript 2}, enabling bacteria to detect changes in exogenous redox potential with high sensitivity and navigate redox gradients. The broad phylogenetic distribution of chemosensory zinc-binding (CZB) domains suggests that this zinc-dependent sensory mechanism is an ancient and widespread strategy for detecting environmental redox gradients that arose early in bacterial evolution and may have been subsequently shaped or expanded in response to increasing atmospheric oxygen associated with the Great Oxygenation Event.

microbiology↗

bioRxiv2024

Hypoxia disrupts circadian rhythms in astrocytes and causes synapse engulfment defects

Astrocytes are emerging as key regulators of neuronal synaptic network maturation and function, through control of synaptic pruning. This is important, because individuals with ASD have excess glutamatergic synapses in the cortex, but the biological mechanisms underlying this phenotype remain unclear. Here, we used human cortical organoids (hCO) derived from induced pluripotent stem cells (hiPSCs), to examine the effect of hypoxia on synapse engulfment in human astrocytes at postnatal-equivalent stages of development. We identified that hypoxia significantly inhibits the synaptosome phagocytosis, and that this phenotype is mediated through disruptions in the astrocytic circadian rhythm molecular pathway and subsequent decreased expression of MEGF10. Lastly, we demonstrated that circadian clock disruptions are sufficient to induce these observed phenotypes even in the absence of hypoxia, both in hCOs and within the mouse hippocampus in vivo. Our study uncovers a novel mechanistic link between hypoxia, circadian rhythms disruptions, and synapse pruning by astrocytes, and provides insight into the pathophysiology of ASD, and other neuropsychiatric diseases. Separately, the demonstration of the presence of circadian rhythms in hCOs opens an unprecedented opportunity to dissect the role of circadian clocks in normal brain development and how it contributes to specific diseases of environmental or genetic origin.

neuroscience↗

bioRxiv2022

Pleiotropic effects of BAFF on the senescence-associated secretome and growth arrest

Senescent cells release a variety of cytokines, proteases, and growth factors collectively known as the senescence-associated secretory phenotype (SASP). Sustained SASP contributes to a pattern of chronic inflammation associated with aging and implicated in many age-related diseases. Here, we investigated the expression and function of the immunomodulatory cytokine BAFF (B-cell activating factor), a SASP protein, in multiple senescence models. We first characterized BAFF production across different senescence models, including senescent human diploid fibroblasts (WI-38, IMR-90) and monocytic leukemia cells (THP-1), and tissues of mice induced to undergo senescence. We then identified IRF1 (interferon response factor 1) as a transcription factor required for promoting BAFF mRNA transcription in senescence. We discovered that suppressing BAFF production decreased the senescent phenotype of both fibroblasts and monocyte-derived THP-1 cells, overall reducing IL6 secretion, SA-{beta}-Gal staining, and {gamma}-H2AX accumulation. Importantly, however, the influence of BAFF on the senescence program was cell type-specific: in monocytes, BAFF promoted the early activation of NF-{kappa}B and general SASP secretion, while in fibroblasts, BAFF contributed to the production and function of TP53 (p53). We propose that BAFF is elevated across senescence models and is a potential target for senotherapy.

cell biology↗

bioRxiv2018

Somatic uniparental disomy with a rare EFL1 variant causes Shwachman-Diamond syndrome through dysregulating ribosomal protein synthesis

Shwachman-Diamond syndrome (SDS; OMIM: #260400) is caused by variants in SBDS (Shwachman-Bodian-Diamond syndrome gene), which encodes a protein that plays an important role in ribosome assembly. Recent reports suggest that recessive variants in EFL1 are also responsible for SDS. However, the precise genetic mechanism that leads to EFL1-induced SDS remains incompletely understood. Here we present three unrelated Korean SDS patients that carry biallelic pathogenic variants in EFL1 with biased allele frequencies, resulting from a bone marrow-specific somatic uniparental disomy (UPD) in chromosome 15. The recombination events generated cells that were homozygous for the relatively milder variant, allowing for the evasion of catastrophic physiological consequences. Still, the milder EFL1 variant was solely able to impair 80S ribosome assembly and induce SDS features in cell line, zebrafish, and mouse models. The loss of EFL1 resulted in a pronounced inhibition of terminal oligo-pyrimidine element-containing ribosomal protein transcript 80S assembly. Therefore, we propose a more accurate pathogenesis mechanism of EFL1 dysfunction that eventually leads to aberrant translational control and ribosomopathy.

genetics↗