Biology subjects

Kim, H.-S.

Publications and source records attributed to Kim, H.-S..

4 recordsLinked to original sources

bioRxiv2018

Pellino 1 Communicates Intercellular Signaling in Chronic Skin Inflammatory Microenvironment

Chronic skin inflammation including psoriasis is a multisystem disease, affecting more than 5% of the general population. Here we show that Pellino 1 (Peli1), a signal-responsive ubiquitin E3 ligase, is highly up-regulated in human psoriatic skin lesions and that increased Peli1 expression correlates with the immunopathogenesis of psoriasis-like chronic skin inflammatory disease. Interestingly, Peli1 directly interacts with interferon regulatory factor 4 (IRF4, a transcription factor that plays pivotal roles in proliferation and cytokine production) and induces lysine 63-mediated ubiquitination. Peli1-mediated IRF4 ubiquitination appears to be a common systemic signaling mechanism shared by lesional keratinocytes, dendritic cells, macrophages, and T cells, generating a feedback relationship between keratinocyte and Th17 cell responses. Conversely, inhibition of Peli1 interferes with IRF4 induction and attenuates immunopathogenic signaling in the psoriasis. In summary, Peli1-mediated ubiquitination is a common immunopathogenic intercellular signaling in psoriasis-like chronic skin inflammatory microenvironment. Thus, targeting Peli1 could be used as a potential strategy for psoriasis treatment.

immunology↗

bioRxiv2018

Repulsive Guidance Molecule Acts in Axon Branching in Caenorhabditis elegans

Repulsive guidance molecules (RGMs) are evolutionarily conserved proteins implicated in repulsive axon guidance. Here we report the function of the Caenorhabditis elegans ortholog DRAG-1 in axon branching. The axons of hermaphrodite-specific neurons (HSNs) branch at the region abutting the vulval muscles and innervate these muscles to control egg laying. The drag-1 mutants exhibited defects in HSN axon branching in addition to a small body size and egg laying-defective phenotype. DRAG-1 expression in the hypodermal cells was required for the branching of these axons. The C-terminal glycosylphosphatidylinositol anchor of DRAG-1 was important for its function. Genetic analyses suggested that the membrane receptor UNC-40, but neither SMA-1/{beta}H-spectrin nor SMA-5/MAP kinase 7, acts in the same pathway with DRAG-1 in HSN branching. We propose that DRAG-1 expressed in the hypodermis signals via the UNC-40 receptor expressed in HSNs to elicit branching activity of HSN axons.

developmental biology↗

bioRxiv2017

Fibronectin type III and intracellular domains of Toll-like receptor 4 interactor with leucine-rich repeats (Tril) are required for developmental signaling

Toll-like receptor 4 interactor with leucine-rich repeats (Tril) is a transmembrane protein that functions as a coreceptor for Toll-like receptors (Tlrs) to mediate innate immune responses in the adult brain. Tril also triggers degradation of the Bmp inhibitor, Smad7, during early embryonic development to allow for normal blood formation. Tril most likely plays additional, yet to be discovered, roles during embryogenesis. In the current studies, we performed a structure-function analysis, which indicated that the extracellular domain, including the fibronectin type III (FN) domain, and the intracellular domain of Tril are required to trigger Smad7 degradation in the early Xenopus embryo. Furthermore, we found that a Tril deletion mutant lacking the FN domain (Tril{Delta}FN) can dominantly inhibit signaling by endogenous Tril when overexpressed in vivo. This finding raises the intriguing possibility that the FN domain functions to bind endogenous Tril/Tlr4 ligands, perhaps including extracellular matrix molecules. We also show that Tril normally cycles between the cell surface and endosomes, and that the Tril extracellular domain is required to retain Tril at the cell surface, while the intracellular domain is required for Tril internalization in Xenopus ectodermal explants. Using a CHO cell aggregation assay, we further show that, unlike other transmembrane proteins that contain leucine rich repeats in the extracellular domain, Tril is not sufficient to mediate homophilic adhesion. Our findings identify Tril{Delta}FN as a valuable tool that can be used to block the function of endogenous Tril in vivo in order to discover additional roles during embryonic development.

cell biology↗

bioRxiv2017

Small molecule-mediated reprogramming of epithelial-mesenchymal transition thereby blocking fibrosis

Fibrotic diseases are major causes of morbidity and mortality, and the epithelial-mesenchymal transition (EMT) plays a central role in the development of tissue/organ fibrosis. We discovered that eupatilin, a member of the chromone scaffold (CS)-containing compounds found ubiquitously in the plant kingdom, completely reversed fibrogenesis in vitro and substantially ameliorated bleomycin-induced lung fibrosis (BILF). Furthermore, eupatilin-induced growth arrest and morphological changes in primary fibroblasts derived from a patient with idiopathic pulmonary fibrosis (IPF). To better understand fibrosis, we established a mouse hepatic stellate cell (HSC) line that was robustly differentiated into myofibroblasts upon treatment with TGF{beta}. HSC-derived fibrogenesis was completely blocked by eupatilin, which caused dramatic morphological changes while inhibiting expression of EMT-related genes. The chemical groups linked to the 2nd carbon (C2), C3, C6, and C7 on the CS of eupatilin were essential for its anti-fibrogenic effects. Unlike eupatilin, pirfenidone failed to block HSC fibrogenesis and did not affect the morphology of HSCs or lung fibroblasts. Although pirfenidone affected local production of TGF{beta}, as reflected by a reduction in the TGF{beta} level in lung lysates of BILF model mice, eupatilin is likely to act via a different therapeutic mechanism. In particular, eupatilin had greater anti-fibrotic capacity and EMT-inhibitory activity and significantly attenuated the phosphorylation of Erk by TGF{beta}. Based on the interactome, Integrin{beta}3 seems to be a major player in integration of TGF{beta} signaling into the eupatilin-mediated anti-fibrosis. Our findings suggest that combinatorial use of eupatilin and pirfenidone may augment the therapeutic efficacy of IPF treatment.

cell biology↗