Biology subjects

Weston, T.

Publications and source records attributed to Weston, T..

3 recordsLinked to original sources

bioRxiv2024

TITINdb2 - Expanding Annotation and Structural Information for Protein Variants in the Giant Sarcomeric Protein Titin

Structured AbstractO_ST_ABSSummaryC_ST_ABSWe present TITINdb2, an update to the TITINdb database previously constructed to facilitate the identification of pathogenic missense variants in the giant protein titin, which are associated with a variety of skeletal and cardiac myopathies. The database and web portal have been substantially revised and include the following new features: (i) an increase in computational annotation from 4 to 20 variant impact predictors, available through a new custom data table dialogue; (ii) thorough structural coverage of single domains with AlphaFold2 predicted models; (iii) newly predicted domain-domain interface annotations; (iv) an expanded in silico saturation mutagenesis incorporating 4 variant impact predictors; (v) a comprehensive overhaul of available data, including population data sources and variants reported pathogenic in the literature; (vi) A curated mapping of existing protein, transcript and chromosomal sequence positions and a new variant conversion tool to translate variants in one format to any other format. Availability and ImplementationDatabase accessible via titindb.kcl.ac.uk/TITINdb/ ContactFranca Fraternali (f.fraternali@ucl.ac.uk) Supplementary InformationAvailable

bioinformatics↗

bioRxiv2024

T cell cholesterol transport is a metabolic checkpoint that links intestinal immune responses to dietary lipid absorption

The intrinsic pathways that control membrane organization in immune cells and the impact of such pathways on cellular function are not well defined. Here we report that the non-vesicular cholesterol transporter Aster-A links plasma membrane (PM) cholesterol availability in T cells to immune signaling and systemic metabolism. Aster-A is recruited to the PM during T-cell receptor (TCR) activation, where it facilitates the removal of newly generated "accessible" membrane cholesterol. Loss of Aster-A leads to excess PM cholesterol accumulation, resulting in enhanced TCR nano-clustering and signaling, and Th17 cytokine production. Finally, we show that the mucosal Th17 response is restrained by PM cholesterol remodeling. Ablation of Aster-A in T cells leads to enhanced IL-22 production, reduced intestinal fatty acid absorption, and resistance to diet-induced obesity. These findings delineate a multi-tiered regulatory scheme linking immune cell lipid flux to nutrient absorption and systemic physiology.

physiology↗

bioRxiv2023

Aster-dependent non-vesicular transport facilitates dietary cholesterol uptake

Intestinal cholesterol absorption is an important contributor to systemic cholesterol homeostasis. Niemann-Pick C1 Like 1 (NPC1L1), the target of the drug ezetimibe (EZ), assists in the initial step of dietary cholesterol uptake. However, how cholesterol moves downstream of NPC1L1 is unknown. Here we show that Aster-B and Aster-C are critical for non-vesicular cholesterol movement in enterocytes, bridging NPC1L1 at the plasma membrane (PM) and ACAT2 in the endoplasmic reticulum (ER). Loss of NPC1L1 diminishes accessible PM cholesterol in enterocytes and abolishes Aster recruitment to the intestinal brush border. Enterocytes lacking Asters accumulate cholesterol at the PM and display evidence of ER cholesterol depletion, including decreased cholesterol ester stores and activation of the SREBP-2 transcriptional pathway. Aster-deficient mice have impaired cholesterol absorption and are protected against diet-induced hypercholesterolemia. Finally, we show that the Aster pathway can be targeted with a small molecule inhibitor to manipulate dietary cholesterol uptake. These findings identify the Aster pathway as a physiologically important and pharmacologically tractable node in dietary lipid absorption. One-Sentence SummaryIdentification of a targetable pathway for regulation of dietary cholesterol absorption

physiology↗