Attenuation of AMPK signaling by ROQUIN promotes T follicular helper cell formation

作者：Roybel R. Ramiscal, Ian A. Parish, Robert S. Lee, Jeffrey J. Babon, Julianna Blagih, Alvin Pratama, Jaime L. Martin, Naomi Hawley, Jean Cappello, Pablo F Nieto, Julia I. Ellyard, Nadia J. Kershaw, Rebecca A. Sweet, Christopher C. Goodnow, Russell G. Jones, Mark A. Febbraio, Carola G. Vinuesa, Vicki Athanasopoulos · 发表于：eLife · 年份：2015 · DOI：10.7554/elife.08698 · 被引用次数：60 · 研究领域：Metabolism, Diabetes, and Cancer、Pancreatic function and diabetes、Calcium signaling and nucleotide metabolism

T follicular helper cells (Tfh) are critical for the longevity and quality of antibody-mediated protection against infection. Yet few signaling pathways have been identified to be unique solely to Tfh development. ROQUIN is a post-transcriptional repressor of T cells, acting through its ROQ domain to destabilize mRNA targets important for Th1, Th17, and Tfh biology. Here, we report that ROQUIN has a paradoxical function on Tfh differentiation mediated by its RING domain: mice with a T cell-specific deletion of the ROQUIN RING domain have unchanged Th1, Th2, Th17, and Tregs during a T-dependent response but show a profoundly defective antigen-specific Tfh compartment. ROQUIN RING signaling directly antagonized the catalytic α1 subunit of adenosine monophosphate-activated protein kinase (AMPK), a central stress-responsive regulator of cellular metabolism and mTOR signaling, which is known to facilitate T-dependent humoral immunity. We therefore unexpectedly uncover a ROQUIN-AMPK metabolic signaling nexus essential for selectively promoting Tfh responses.