Year: 2025
Type: article
Abstract: 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.
Source: Science
Authors: Yajing Gao, John P. Kennelly, Xu Xiao, Emily Whang, Alessandra Ferrari, Alexander H. Bedard, Julia J. Mack, Alexander Nguyen, Sonal Srikanth, Thomas Weston, Lauren F. Uchiyama, Whitaker Cohn, Danielle H. Cho, Min Sub Lee, Julian Whitelegge, Yousang Gwack, Stephen G. Young, Steven J. Bensinger, Peter Tontonoz
Institution: University of California, Los Angeles
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: American Diabetes Association, American Heart Association, Damon Runyon Cancer Research Foundation, Fondation Leducq, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development, California NanoSystems Institute
Awards: The Nuclear Receptor-Aster Pathway in Enterohepatic Metabolism, G1063394308, G1287270537, G1736624471, New approaches for understanding lipid movement in health and disease, New pathways in intestinal cholesterol transport, G2814903553, G343705321, G3618943978, G50039297, G5814634182, G9000031392, G9000034272, UCLA Child Health Research Career Development Award, Mechanistic link between mitochondrial cristae integrity and Th1 responses
OpenAlex ID: W4415037562