Biology subjects

Kim, Y. H.

Publications and source records attributed to Kim, Y. H..

25 records · Page 2Linked to original sources

bioRxiv2020

Size-dependent protein segregation creates a spatial switch for Notch and APP signaling

Aberrant cleavage of Notch by {gamma}-secretase is implicated in numerous diseases, but how cleavage is regulated in space and time is unclear. Here, we report that cadherin-based adherens junctions (cadAJs) are sites of high cell-surface {gamma}-secretase activity, as well as sites of constrained physical space that excludes {gamma}-secretase substrates having large extracellular domains (ECDs) like Notch. ECD shedding initiates drastic spatial relocalization of Notch to cadAJs, allowing enzyme-substrate interactions and downstream signaling. Spatial mutations by adjusting the ECD size or the physical constraint alter signaling. Dysregulation of this spatial switch promotes precocious differentiation of ventricular zone neural progenitor cells in vivo. We show the generality of this spatial switch for amyloid precursor protein proteolysis. Thus, cadAJs create spatially distinct biochemical compartments regulating cleavage events involving {gamma}-secretase and preventing aberrant activation of receptors. One Sentence SummaryNotch cleavage by {gamma}-secretase is regulated through dynamic spatial control of receptors, adhesion molecules, and activating proteases

cell biology↗

bioRxiv2020

Deletion of immune evasion genes provides an effective vaccine design for tumor-associated herpesviruses

Vaccines based on live attenuated viruses often induce broad, multifaceted immune responses. However, they also usually sacrifice immunogenicity for attenuation. It is particularly difficult to elicit an effective vaccine for herpesviruses due to an armament of immune evasion genes and a latent phase. Here, to overcome the limitation of attenuation, we developed a rational herpesvirus vaccine in which viral immune evasion genes were deleted to enhance immunogenicity while also attaining safety. To test this vaccine strategy, we utilized murine gammaherpesvirus-68 (MHV-68) as a proof-of-concept model for the cancer-associated human {gamma}-herpesviruses, Epstein-Barr virus and Kaposi sarcoma-associated herpesvirus. We engineered a recombinant MHV-68 virus by targeted inactivation of viral antagonists of type I interferon (IFN-I) pathway and deletion of the latency locus responsible for persistent infection. This recombinant virus is highly attenuated with no measurable capacity for replication, latency, or persistence in immunocompetent hosts. It stimulates robust innate immunity, differentiates virus-specific memory T cells, and elicits neutralizing antibodies. A single vaccination affords durable protection that blocks the establishment of latency following challenge with the wild type MHV-68 for at least six months post-vaccination. These results provide a novel approach to effective vaccination against cancer-associated herpesviruses through the elimination of latency and key immune evasion mechanisms from the pathogen.

microbiology↗

bioRxiv2019

6-O-galloylsalidroside, an active ingredient from Acer tegmentosum, ameliorates alcoholic steatosis and liver injury in a mouse model of chronic ethanol consumption

We previously reported that Acer tegmentosum extract, which is traditionally used to treat liver disease in Korea, may help reduce fat accumulation, improve liver metabolism, and suppress inflammation in alcoholic liver disease. The active ingredient was found to be 6-O-galloylsalidroside, which was isolated from the methanol extract of A. tegmentosum. We hypothesized that 6-O-galloylsalidroside extracted from A. tegmentosum may help protect from liver damage and attenuate hepatic fat accumulation associated with chronic alcohol consumption. In the present study, we aimed to investigate whether 6-O-galloylsalidroside can regulate alcoholic fatty liver and liver injury in mice. For this purpose, mice were fed with Lieber-DeCarli 5% ethanol diet for 11 days to induce steatosis and liver injury. Oral 6-O-galloylsalidroside was administered once a day for 11 days. Intrahepatic lipid accumulation caused by alcohol consumption was measured using in vivo 1H magnetic resonance imaging. Hepatic steatosis was observed histologically in tissue samples stained with hematoxylin and eosin, as well as Oil Red O. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured, as well as the triglyceride content in liver homogenates. On magnetic resonance spectroscopy, 6-O-galloylsalidroside appeared to alleviate alcohol-induced steatosis, which was reflected in decreased hepatic and serum triglyceride levels despite ethanol feeding. Furthermore, 6-O-galloylsalidroside treatment was associated with decreased RNA expression of Cd36, which plays an important role in the development of alcoholic steatosis through the hepatic de novo lipogenesis pathway. Furthermore, treatment with 6-O-galloylsalidroside inhibited the expression of cytochrome P4502E1 and attenuated hepatocellular damage, reflected in reduced ALT and AST levels. These findings suggest that 6-O-galloylsalidroside extracted from A. tegmentosum might serve as a bioactive agent for treating alcoholic fatty liver and liver damage.

biochemistry↗

bioRxiv2019

C9orf72-associated arginine-rich dipeptide repeats induce RNA-dependent accumulation of Staufen in nucleus

Accumulation of RNA in the nucleus is one of the pathological features of C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD), yet its potential toxic cellular consequences remain largely undefined. RNA accumulated in the nucleus may interact with and increase nuclear localization of RNA-binding proteins (RBPs). Here, we show in C9-ALS/FTD Drosophila melanogaster model that Staufen, a double-stranded RBP normally localized in cytoplasm, accumulates in the nucleus, which is in contrast to many nuclear-localized RBPs, such as TDP-43 and FUS, whose cytoplasmic accumulation is thought to be a pathological hallmark of ALS/FTD. We found that in Drosophila neurons expressing arginine-rich dipeptide repeat proteins (DPRs), Staufen accumulated in the nucleus in an RNA-dependent manner. In the nucleus, Staufen localized closely to, and potentially interacts with, heterochromatin and nucleolus in Drosophila C4 da neurons expressing poly(PR), a proline-arginine (PR) DPR. PR toxicity in C4 da neurons increased Fibrillarin staining in the nucleolus, which was enhanced by stau heterozygous mutation. Furthermore, knockdown of fib exacerbated retinal degeneration mediated by PR toxicity, which suggests that increased amount of Fibrillarin by stau heterozygous mutation is protective. Heterozygotic mutation of stau could also mitigate retinal degeneration and rescue viability of flies exhibiting PR toxicity. Taken together, our data show that nuclear accumulation of cytoplasmic protein, such as Staufen, may also be an important pathological feature of C9-ALS/FTD.\n\nAuthor summaryCytoplasmic accumulation of nuclear RNA-binding proteins (RBPs) is one of the common pathological features of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In C9orf72-associated ALS/FTD fly model, we found that Staufen, a double-stranded (ds) RBP normally localized mostly in cytoplasm, accumulates in the nucleus in an RNA-dependent manner. Next, we checked wherein the nucleus Staufen accumulates and found that Staufen partially co-localizes with heterochromatin and nucleolus. Interestingly, the expression of Fibrillarin, a nucleolar protein, was significantly increased by C9orf72-derived PR toxicity and further augmented by reduction in stau dosage, the gene encoding Staufen. When we knocked down fib, the gene encoding Fibrillarin, PR-induced retinal degeneration was exacerbated. This indicates that increased Fibrillarin expression by stau dosage reduction is protective. Furthermore, when we reduced stau dosage in flies presenting PR toxicity, their retinal degeneration and viability were largely rescued. Based on these data, we suggest that nuclear accumulation of Staufen is an important feature of C9-ALS/FTD and suggest that reducing stau dosage is a promising therapeutic target.

genetics↗

bioRxiv2019

Resolvin D3 controls mouse and human nociceptive functions and preclinical progression of psoriasis

Psoriasis is a chronic inflammatory skin disease caused by a complex interplay between the immune and nervous systems. Here, we found that resolvin D3 (RvD3) significantly prevented both skin inflammation and itch in a preclinical animal model of psoriasis induced by repeated applications of imiquimod. We also found that RvD3 anti-psoriatic effects resulted from the inhibition of nociceptive functions, which inhibition was replicated in human nociceptive neurons. We conclude that RvD3 and targeting nociceptive functions are promising strategies to treat psoriasis.

neuroscience↗

bioRxiv2019

Dose assessment in dental cone beam computed tomography: comparison of optically stimulated luminescence dosimetry with the Monte Carlo method

The usage and the model variety of CBCT machine has been rapidly increasing, the dose evaluation of individual devices became an important issue. Patient dose from CBCT was assessed with two different methods, optically stimulated luminescence dosimeter (OSLD) measured and monte carlo (MC) simulation, in four different examination modes. Through the measurement process and obtained value, more practical and efficient method in acquiring CBCT effective dose would be suggested. Twenty-five OSLD were calibrated and equipped in human phantom of head and neck organs. This was exposed on 2 CBCT units, CS9300 (Carestream Dental LLC, Atlanta, Georgia) and RAYSCAN + (Ray Co. Ltd, Hwaseong-si, Korea) with 2 different examination modes. Dose recorded in dosimetry was obtained and organ dose as well as an effective dose were obtained in each units of examination modes. Those values were also calculated using MC software, PCXMC (STUK, Helsinki, Finland). The organ doses and effective doses from both methods were compared by each examination mode of individual unit. OSLD measured effective dose value was higher than that obtained with MC method in each examination mode, except dual jaw mode of CS9300. The percent difference of effective dose between the two methods were ranged from 4.0 to 14.3 %. The dose difference between the methods was decreased as the examination FOV decreased. Organ dose values were varied according to the method, while overall trend was similar in both methods. The organs showing high dose were mostly consistent in both methods. In this study, the effective dose obtained by OSLD measurement and MC simulation were compared and both methods were described in detail. Consequently, as relatively efficient and easy-handling method, we carefully suggest MC simulation for further dose evaluation.

scientific communication and education↗

bioRxiv2018

Peroxiredoxin-mediated HMGB1 oxidation and secretion in response to inflammatory stimuli

The nuclear protein HMGB1 (high mobility group box 1) is secreted by monocytesmacrophages in response to inflammatory stimuli and serves as a danger-associated molecular pattern. Acetylation and phosphorylation of HMGB1 are implicated in the regulation of its nucleocytoplasmic translocation for secretion, although inflammatory stimuli are also known to induce H2O2 production. Here we show that H2O2-induced oxidation of HMGB1 that results in formation of an intramolecular disulphide bond between Cys23 and Cys45 is necessary and sufficient for its nucleocytoplasmic translocation and secretion. The oxidation is catalysed by peroxiredoxin I (PrxI) and PrxII, which are first oxidized by H2O2 and then transfer their disulphide oxidation state to HMGB1. The disulphide form of HMGB1 showed a higher affinity for the nuclear exportin CRM1 compared with the reduced form. Lipopolysaccharide (LPS)-induced HMGB1 secretion was greatly attenuated in macrophages derived from PrxI or PrxII knockout mice, as was the LPS-induced increase in serum HMGB1 levels in these mice.

immunology↗