Biology subjects

Choi, Y. B.

Publications and source records attributed to Choi, Y. B..

8 recordsLinked to original sources

bioRxiv2024

ZFAND6 is a subunit of a TRAF2-cIAP E3 ubiquitin ligase complex essential for mitophagy

The A20 ubiquitin-editing enzyme is a critical negative regulator of NF-{kappa}B signaling and inflammation. While the mechanisms by which A20 restricts inflammation have been extensively studied, the physiological functions of other A20-like proteins are largely unknown. Here, we report a previously unknown function of the A20 family member ZFAND6 as a novel regulator of mitophagy. Deletion of ZFAND6 in bone marrow-derived macrophages (BMDMs) promotes the upregulation of reactive oxygen species (ROS) and the accumulation of damaged mitochondria due to impaired mitophagy. Consequently, mitochondrial DNA (mtDNA) is released into the cytoplasm, triggering the spontaneous expression of interferon-stimulated genes (ISGs) in a cGAS-STING dependent manner, which leads to enhanced viral resistance in vitro. However, mice lacking ZFAND6 exhibit increased morbidity and mortality upon challenge with a sublethal dose of influenza A virus (IAV) due to impaired myeloid cell activation and diminished type I IFN signaling. Mechanistically, ZFAND6 bridges a TRAF2-cIAP1 interaction, which is required for the initiation of ubiquitin-dependent mitophagy. Our results suggest that ZFAND6 is a subunit of a TRAF2-cIAP E3 ligase complex that promotes the clearance of damaged mitochondria by mitophagy to maintain mitochondrial homeostasis.

immunology↗

bioRxiv2021

Individual differences in visual search performance extend from artificial arrays to naturalistic environments.

Visual search is a universal human activity in naturalistic environments. Traditionally, visual search is investigated under tightly controlled conditions, where head-restricted participants locate a minimalistic target in a cluttered array presented on a computer screen. Do classic findings of visual search extend to naturalistic settings, where participants actively explore complex, real-world scenes? Here, we leverage advances in virtual reality (VR) technology to relate individual differences in classic visual search paradigms to naturalistic search behavior. In a naturalistic visual search task, participants looked for an object within their environment via a combination of head-turns and eye-movements using a head-mounted display. Then, in a classic visual search task, participants searched for a target within a simple array of colored letters using only eye-movements. We tested how set size, a property known to limit visual search within computer displays, predicts the efficiency of search behavior inside immersive, real-world scenes that vary in levels of visual clutter. We found that participants search performance was impacted by the level of visual clutter within real-world scenes. Critically, we also observed that individual differences in vi1-3sual search efficiency in classic search predicted efficiency in real-world search, but only when the comparison was limited to the forward-facing field of view for real-world search. These results demonstrate that set size is a reliable predictor of individual performance across computer-based and active, real-world visual search behavior.

neuroscience↗

bioRxiv2021

Phosphorylation of the selective autophagy receptor TAX1BP1 by canonical and noncanonical IκB kinases promotes its lysosomal localization and clearance of MAVS aggregates

TAX1BP1 is a selective autophagy receptor which inhibits NF-{kappa}B and RIG-I-like receptor (RLR) signaling to prevent excessive inflammation and maintain homeostasis. Selective autophagy receptors such as p62/SQSTM1 and OPTN are phosphorylated by the noncanonical I{kappa}B kinase TBK1 to stimulate their selective autophagy function. However, it is unknown if TAX1BP1 is regulated by TBK1 or other kinases under basal conditions or during RNA virus infection. Here, we found that the noncanonical I{kappa}B kinases TBK1 and IKKi phosphorylate TAX1BP1 to regulate its basal turnover, whereas the canonical I{kappa}B kinase IKK and the core autophagy factor ATG9 play essential roles in RNA virus-mediated TAX1BP1 autophagosomal degradation. TAX1BP1 phosphorylation by canonical and noncanonical I{kappa}B kinases promotes its localization to lysosomes resulting in its degradation. Furthermore, TAX1BP1 plays a critical role in the clearance of MAVS aggregates, and phosphorylation of TAX1BP1 augments its MAVS aggrephagy function. Together, our data support a model whereby I{kappa}B kinases license TAX1BP1 selective autophagy function to inhibit MAVS and RLR signaling. Author SummaryThe RIG-I-like receptor (RLR) pathway induces type I interferon (IFN) and proinflammatory cytokines in response to RNA virus infection. MAVS is a mitochondrial adaptor protein in the RLR pathway that forms prion-like aggregates upon activation; however, how MAVS aggregates are cleared to restore homeostasis is unclear. Autophagy is a lysosomal degradation pathway important for the clearance of potentially cytotoxic protein aggregates that could induce inflammation and/or cell death. TAX1BP1 is a selective autophagy receptor that inhibits RLR signaling, but the precise mechanisms remain unknown. Here, we found that TAX1BP1 is a substrate for multi-site phosphorylation by canonical and noncanonical I{kappa}B kinases which triggered its lysosomal localization and degradation. We also found that TAX1BP1 was critical for the clearance of MAVS aggregates in a phosphorylation-dependent manner. Overall, our data suggest that phosphorylation serves a key regulatory function for TAX1BP1 to inhibit RLR signaling.

immunology↗

bioRxiv2020

Atypical Mediofrontal Theta Oscillations Underlying Cognitive Control in Kindergarteners with Autism Spectrum Disorder

BackgroundChildren with autism spectrum disorder (ASD) often exhibit deficits in cognitive control. Neuroimaging approaches have implicated disruptions to medio-frontal cortex (MFC) structure and function. However, prior work has not directly tested whether young children with ASD exhibit disruptions to task-related theta oscillations thought to arise from the MFC. MethodsForty-three children with ASD and 24 age- and gender-matched typically developing (TD) peers performed a child-friendly Go/No-go task while 64-channel electroencephalography (EEG) was recorded at kindergarten-entry. Time-frequency approaches were employed to assess the magnitude of mediofrontal theta oscillations immediately following error (vs. correct) responses ("early theta"), as well as later emerging theta oscillations ("late theta"). We tested whether error-related mediofrontal theta oscillations differed as a function of diagnosis (ASD/typical) and timing (early/late theta). Additionally, links to social and academic outcomes were tested. ResultsOverall, children showed increased theta power following error vs. correct responses. Compared to TD children, children with ASD exhibited a selective reduction in error-related mediofrontal theta power during the late theta time window. There were no significant group differences for early theta power. Moreover, reduced error-related theta power during the late, but not early, time window significantly predicted poorer academic and social skills. ConclusionsKindergarteners with ASD demonstrated a selective reduction in error-related mediofrontal theta power during a relatively late time window, which is consistent with impairments in specific cognitive processes that recruit top-down control. Targeting these particular cognitive control processes via intervention prior to school-entry may promote more successful functional outcomes for children with ASD.

neuroscience↗

bioRxiv2020

The E3/E4 ubiquitin conjugation factor UBE4B interacts with and ubiquitinates the HTLV-1 Tax oncoprotein to promote NF-kB activation

Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATLL), and the neurological disease HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 Tax protein persistently activates the NF-{kappa}B pathway to enhance the proliferation and survival of HTLV-1 infected T cells. Lysine 63 (K63)-linked polyubiquitination of Tax provides an important regulatory mechanism that promotes Tax-mediated interaction with the IKK complex and activation of NF-{kappa}B; however, the host proteins regulating Tax ubiquitination are largely unknown. To identify novel Tax interacting proteins that may regulate its ubiquitination we conducted a yeast two-hybrid screen using Tax as bait. This screen yielded the E3/E4 ubiquitin conjugation factor UBE4B as a novel binding partner for Tax. Here, we confirmed the interaction between Tax and UBE4B in mammalian cells by co-immunoprecipitation assays and demonstrated colocalization by proximity ligation assay and confocal microscopy. Overexpression of UBE4B specifically enhanced Tax-induced NF-{kappa}B activation, whereas knockdown of UBE4B impaired Tax-induced NF-{kappa}B activation and the induction of NF-{kappa}B target genes in T cells and ATLL cell lines. Furthermore, depletion of UBE4B with shRNA resulted in apoptotic cell death and diminished the proliferation of ATLL cell lines. Finally, overexpression of UBE4B enhanced Tax polyubiquitination, and knockdown or CRISPR/Cas9-mediated knockout of UBE4B attenuated both K48- and K63-linked polyubiquitination of Tax. Collectively, these results implicate UBE4B in HTLV-1 Tax polyubiquitination and downstream NF-{kappa}B activation. Author SummaryInfection with the retrovirus HTLV-1 leads to the development of either CD4+CD25+ leukemia/lymphoma (ATLL) or a demyelinating neuroinflammatory disease (HAM/TSP) in a subset of infected individuals. The HTLV-1 Tax protein is a regulatory protein which regulates viral gene expression and persistently activates cellular signaling pathways such as NF-{kappa}B to drive the clonal expansion and longevity of HTLV-1 infected CD4+ T cells. Polyubiquitination of Tax is a key mechanism of NF-{kappa}B activation by assembling and activating I{kappa}B kinase (IKK) signaling complexes; however, the host factors regulating Tax ubiquitination have remained elusive. Here, we have identified the E3/E4 ubiquitin conjugation factor UBE4B as a novel Tax binding protein that promotes both K48- and K63-linked polyubiquitination of Tax. Knockdown or knockout of UBE4B impairs Tax-induced NF-{kappa}B activation and triggers apoptosis of HTLV-1 transformed cells. Therefore, UBE4B is an integral host factor that supports HTLV-1 Tax polyubiquitination, NF-{kappa}B activation and cell survival.

microbiology↗

bioRxiv2019

Sarcopenia is an independent predictor of hospitalization in chronic kidney disease outpatients

BackgroundPatients with chronic kidney disease (CKD) experience much more marked and earlier muscle wasting than subjects who do not have chronic illnesses. However, a few studies that have examined sarcopenia have been reported in CKD patients. We investigated the prevalence of sarcopenia in predialysis and dialysis outpatients with CKD and explored its relationship with the clinical outcomes.\n\nMeasurementsSarcopenia was defined as reduced muscle strength accompanied by decreased adjusted appendicular skeletal muscle (ASM), while those patients who exhibited only one of these characteristics were categorized as presarcopenic patients. ASM was measured by bioimpedence analysis, and muscle strength was evaluated by handgrips. ASM was adjusted by weight (ASM/wt). Patients were prospectively followed for up to 2 years.\n\nResultsOne hundred seventy-nine patients were recruited (114 male and 65 female patients who were classified into 103 predialysis patients and 76 dialysis patients, with 44.7% having diabetes). Their mean age was 60.6 {+/-} 13.5 years old. The prevalence of sarcopenia was 9.5%, while 55.9% of the patients were categorized as presarcopenic. The ASM/wt index showed significant correlations with age, handgrip strength, HOMA-IR and frailty scores. Multivariate Cox proportional hazards models demonstrated that the risk of hospitalization was significantly higher for patients with presarcopenia [hazard ratio (HR), 2.48; 95% confidence interval (CI), 1.180-5.230], and the risk of hospitalization was much higher for patients with sarcopenia than for patients in the nonsarcopenic group (HR, 9.11; 95% CI, 2.295-25.182)\n\nConclusionsSarcopenia and presarcopenia, which were defined using the ASM/wt index and handgrip strength, predicted a poorer, hospitalization-free survival in CKD patients

scientific communication and education↗

bioRxiv2018

Activation of NIX-mediated mitophagy and replication by an interferon regulatory factor homologue of human herpesvirus

Viral control of mitochondrial quality and content has emerged as an important mechanism for counteracting the host response to virus infection. Despite the knowledge of this crucial function of some viruses, little is known about how herpesviruses regulate mitochondrial homeostasis during infection. Human herpesvirus 8 (HHV-8) is an oncogenic virus causally related to AIDS-associated malignancies. Here, we found that HHV-8-encoded viral interferon regulatory factor 1 (vIRF-1) promotes mitochondrial clearance by activating mitophagy to support virus replication. Genetic interference with vIRF-1 expression or targeting to the mitochondria inhibits HHV-8 replication-induced mitophagy and leads to an accumulation of mitochondria. Moreover, vIRF-1 binds directly to a mitophagy receptor, NIX, on the mitochondria and activates NIX-mediated mitophagy to promote mitochondrial clearance. Genetic and pharmacological interruption of vIRF-1/NIX-activated mitophagy inhibits HHV-8 productive replication. In short, our findings uncover an essential role of vIRF-1 in mitophagy activation for successful lytic replication of HHV-8.

microbiology↗

bioRxiv2018

Neural Dynamics of Executive Function in Cognitively-able Kindergarteners with Autism Spectrum Disorders (ASD) as Predictors of Concurrent Academic Achievement: Preliminary Study

Although electrophysiological (EEG) measures of executive functions (EF) (e.g. error monitoring) have been used to predict academic achievement in typically developing (TD) children, work investigating a link between error monitoring, and academic skills in children with autism spectrum disorder (ASD) is limited. In the current study, we employed traditional electrophysiological and advanced time-frequency methods, combined with principal components analyses, to extract neural activity related to error monitoring, and tested their relations to academic achievement in cognitively-able kindergarteners with ASD. Thirty-five cognitively-able kindergarteners with ASD completed academic assessments and the child-friendly \"Zoo Game\" Go/No-go task at school entry. The Go/No-go task successfully elicited an error-related negativity (ERN) and error positivity (Pe) in children with ASD as young as 5 years at medio-frontal and posterior electrode sites, respectively. We also observed increased response-related theta power during errors relative to correct trials at medio-frontal sites. Both larger Pe and theta power significantly predicted concurrent academic achievement after controlling for behavioral performance on the Zoo Game and IQ. These results suggest that the use of time frequency EEG analyses, combined with traditional ERP measures, may provide new opportunities to investigate neurobiological mechanisms of EF and academic achievement in young children with ASD.

neuroscience↗