Biology subjects

Song, H. K.

Publications and source records attributed to Song, H. K..

5 recordsLinked to original sources

bioRxiv2026

The anatomical compartment defines distinct immune remodeling within human visceral adipose tissue during aging

Age-associated inflammation varies across tissues, but whether distinct visceral adipose tissue (VAT) depots undergo inflammatory remodeling in a depot-specific manner remains unclear. Here we profiled human peri-organ VAT, comparing kidney-associated fat (KF, from kidney transplantation donors) and gallbladder-associated fat (GBF, from asymptomatic cholecystectomy patients with incidental polyps), using single-cell RNA sequencing, flow cytometry, intracellular protein profiling and in situ analysis. GBF showed broad tissue-residency and granzyme K-associated remodeling across conventional, regulatory and innate-like lymphocyte compartments, whereas KF showed stronger B cell remodeling, greater myeloid representation and more compartmentalized changes within resident effector-like CD8+ T cell states. We further identified age-associated CD20+ T cells with features consistent with local B-T cell interaction and an antigen-experienced, granzyme K-associated inflammatory memory phenotype. In situ analysis revealed age-associated myeloid accumulation and crown-like structure remodeling, accompanied by distinct myeloid inflammatory programs in KF and GBF. Finally, depot-specific immune signatures associated with clinical indices of adjacent kidney and liver function. These findings indicate that age-associated distinct immune programs within peri-organ VAT depots track with local tissue context and the state of the adjacent organ.

immunology↗

bioRxiv2024

Effect of Stroma-directed Drugs in Combination with Chemotherapy Against Pancreatic Cancer- a Preclinical Study

Cytotoxic chemotherapy plays an important role for extending the survival of patients with pancreatic ductal adenocarcinoma (PDAC). To enhance the efficacy of chemotherapy for eradicating the cancer cells, we have compared the standard care chemotherapy (combination of nab-paclitaxel, gemcitabine and cisplatin, NGC) versus NGC plus stroma-directed agents (calcipotriol and losartan, respectively) in a genetically engineered mouse model of PDAC. Over a 2-week study period, MRI was conducted to measure the tumor size and to test the sensitivity of imaging markers derived from diffusion-weighted imaging (DWI), dynamic contrast enhanced MRI (DCE) and magnetization transfer ratio (MTR) for assessing the tumor cellularity and stromal changes. Detailed immunohistochemistry and preliminary single cell RNA sequencing (scRNAseq) study were applied to tumor tissues collected upon euthanasia on day-14. Our major findings are: 1. Compared the untreated controls, NGC chemotherapy induced significant tumor growth inhibition and stromal changes including pronounced reduction of fibroblast associated protein (FAP) level accompanied by increased matrix collagen content, significantly reduced microvascular permeability revealed by DCE corroborated with reduced microvascular density. 2. Losartan+NGC significantly enhanced inhibition of tumor growth beyond NGC and increased lymphocytes infiltration in the tumor which may contribute to enhanced cancer cells eradication. 3. NGC treatment enriched the fraction of mesenchymal (M) subtype while reducing the epithelial (E) subtype of cancer cells compared to the controls, and this trend was reversed by calcipotriol+NGC. In conclusion, our study captured changes in cancer cell and tumor microenvironment in response to chemo stromal therapy versus chemotherapy alone with mechanistic insights.

cancer biology↗

bioRxiv2024

The N-degron pathway governs autophagy to promote thermotolerance in Arabidopsis

Autophagy is a vital process that enables plants to adapt to various environmental changes. During heat stress (HS), misfolded and denatured proteins accumulate in cells, necessitating autophagy for their removal. Here, we show that a core autophagy component ATG8a is targeted for degradation via the Arg/N-degron pathway. ATG8a is expressed as two alternatively spliced transcripts encoding ATG8a isoforms, namely ATG8a(S) and ATG8a(L), with distinct N-termini. While ATG8a(S) remains stable, ATG8a(L) is N-terminally processed to expose the Arg/N-degron, leading to its degradation. UBR7, identified as an N-recognin, is responsible for ubiquitination and proteasomal degradation of ATG8a(L). Notably, ATG8a(S) and ATG8a(L) show dynamic expression patterns, fluctuating ATG8a levels during the HS and recovery periods. Our findings highlight the crucial role of ATG8a turnover in conferring thermotolerance, which is governed by Arg/N-degron-mediated regulation. Understanding the molecular basis of ATG8a stability will provide valuable insights into plant resilience to HS under changing climatic conditions.

plant biology↗

bioRxiv2022

Structural analyses of the plant PRT6-UBR box in the Cys-Arg/N-degron pathway and insights into the plant submergence response

The submergence response in higher plants is highly dependent on the protein stability of group VII ethylene response factors, which are primarily degraded through the oxygen-dependent Cys-Arg branch of the N-degron pathway of targeted proteolysis. Knockout of PRT6, an E3 ligase and a vital component of the N-degron pathway, improves submergence tolerance in Arabidopsis and barley but is associated with side effects such as germination deficiency. In this study, we determined structures of rice and Arabidopsis PRT6-UBR box in complex with various Arg/N-degron related peptides. We identified two highly conserved motifs in the plant PRT6-UBR box, which is responsible for Cys-Arg/N-degron recognition. Structural and mutagenesis studies revealed the importance of two conserved motifs for Cys-Arg/N-degron recognition. The phenotype of Arabidopsis seedlings with PRT6-UBR mutants in these newly identified conserved motifs showed superior submergence survival suggesting that rational manipulation of the PRT6-UBR box can improve flood tolerance. Our results provide an engineering platform for generating crops with improved submergence tolerance.

biochemistry↗

bioRxiv2021

Opening the side exit pores of ClpP by lowering the pH of proteolytic chamber coupled with substrate hydrolysis

The ClpP serine peptidase is a tetradecameric degradation machine involved in many physiological processes. It becomes a competent ATP-dependent protease with Clp-ATPases. Small chemical compounds, acyldepsipeptides (ADEPs), are known to cause dysregulation and activation of ClpP without ATPases, and have potential as novel antibiotics. Previously, structural studies of ClpP from various species revealed the structural details, conformational changes, and activation mechanism. Although product release by the side exit pores has been proposed, the detailed driving force for product release remains elusive. Here, we report crystal structures of ClpP from Bacillus subtilis (BsClpP) in unforeseen ADEP-bound states. Cryo-electron microscopy structures revealed various conformational states at different pH conditions. To understand the conformational change for product release, we investigated the relationship between substrate hydrolysis and the pH lowering process. Our data, together with previous findings, provide insight into the molecular mechanism of product release by ClpP self-compartmentalizing protease.

biochemistry↗