Biology subjects

lin, y.

Publications and source records attributed to lin, y..

3 recordsLinked to original sources

bioRxiv2025

TRiC-assisted folding of class I HDAC family proteins regulated by distinct co-chaperone and cofactor networks

Class I histone deacetylases (HDACs), including HDAC1, HDAC2, HDAC3, and HDAC8, are essential for diverse cellular processes. Although the chaperonin TRiC is implicated in the activation of class I HDACs, the underlying mechanisms remain elusive. Using cryo-electron microscopy (cryo-EM), cross-linking mass spectrometry (XL-MS), and biochemistry analyses, we established class I HDACs as novel TRiC substrates and elucidate TRiC-assisted folding of HDAC1 and HDAC3 during its ATPase cycle, orchestrated by distinct co-chaperone and cofactor networks. In the closed TRiC chamber, both HDAC1 and HDAC3 adopt near-native states with shared binding interfaces. However, their open-state configurations diverge: Hsp70 and PDCD5 engage atop and within TRiC, respectively, for HDAC3, whereas prefoldin (PFD) binds atop TRiC for HDAC1, suggesting roles in substrate delivery and folding modulation. Furthermore, an unexpected bent conformation of CCT4, detected in TRiC-HDAC1 complex, may facilitate co-chaperone dissociation from TRiC. In contrast, HDAC8 folds independently of TRiC. Our study reveals the mechanism governing TRiC-assisted folding of class I HDACs in orchestration of dynamic co-chaperone/cofactor network, shielding new lights on the sophisticated regulatory landscape of TRiC, and open promising avenues for designing peptides or small molecules to selectively modulate TRiC-assisted folding of class I HDACs and other substrates.

molecular biology↗

bioRxiv2021

Histone neutralization in a rat model of acute lung injury induced by double-hit lipopolysaccharide

BackgroundAcute respiratory distress syndrome (ARDS) remains a challenge because of its high morbidity and mortality. Circulation histones levels in ARDS patients were correlated to disease severity and mortality. This study examined the impact of histone neutralization in a rat model of acute lung injury (ALI) induced by a lipopolysaccharide (LPS) double-hit. MethodsSixty-eight male Sprague-Dawley rats were randomized to sham (N=8, received saline only) or LPS (N=60). The LPS double-hit consisted of a 0.8 mg/kg intraperitoneal injection followed after 16 hours by 5 mg/kg intra-tracheal nebulized LPS. The LPS group was then randomized into five groups: LPS only (N=12); LPS + 5, 25, or 100 mg/kg intravenous STC3141 every 8 hours (LPS+L, LPS+M, LPS+H, respectively, each N=12); or LPS + intraperitoneal dexamethasone 2.5 mg/kg every 24 hours for 56 hours (LPS+D, N=12) The animals were observed for 72 hours. ResultsLPS animals developed ALI as suggested by lower oxygenation, lung edema formation, and histological changes compared to the sham animals. Compared to the LPS group, LPS+H and +D animals had significantly lower circulating histone levels; only the LPS+D group had significantly lower bronchoalveolar lavage fluid (BALF) histone concentrations. The LPS+L, +M, +H and +D groups had improved oxygenation compared to the LPS group and the LPS+H and +D groups had a lower lung wet-to-dry ratio. All animals survived. ConclusionNeutralization of histone using STC3141, especially at high dose, had similar therapeutic effects to dexamethasone in this LPS double-hit rat ALI model, with significantly decreased circulating histone concentration, improved oxygenation, and decreased lung edema formation.

pharmacology and toxicology↗

bioRxiv2019

INeo-Epp: T-cell HLA class I immunogenic or neoantigenic epitope prediction via random forest algorithm based on sequence related amino acid features

In silico T-cell epitope prediction plays an important role in immunization experimental design and vaccine preparation. Currently, most epitope prediction research focuses on peptide processing and presentation, e.g. proteasomal cleavage, transporter associated with antigen processing (TAP) and major histocompatibility complex (MHC) combination. To date, however, the mechanism for immunogenicity of epitopes remains unclear. It is generally agreed upon that T-cell immunogenicity may be influenced by the foreignness, accessibility, molecular weight, molecular structure, molecular conformation, chemical properties and physical properties of target peptides to different degrees. In this work, we tried to combine these factors. Firstly, we collected significant experimental HLA-I T-cell immunogenic peptide data, as well as the potential immunogenic amino acid properties. Several characteristics were extracted, including amino acid physicochemical property of epitope sequence, peptide entropy, eluted ligand likelihood percentile rank (EL rank(%)) score and frequency score for immunogenic peptide. Subsequently, a random forest classifier for T cell immunogenic HLA-I presenting antigen epitopes and neoantigens was constructed. The classification results for the antigen epitopes outperformed the previous research (the optimal AUC=0.81, external validation data set AUC=0.77). As mutational epitopes generated by the coding region contain only the alterations of one or two amino acids, we assume that these characteristics might also be applied to the classification of the endogenic mutational neoepitopes also called neoantigens. Based on mutation information and sequence related amino acid characteristics, a prediction model of neoantigen was established as well (the optimal AUC=0.78). Further, an easy-to-use web-based tool INeo-Epp was developed (available at http://www.biostatistics.online/INeo-Epp/neoantigen.php)for the prediction of human immunogenic antigen epitopes and neoantigen epitopes.

immunology↗