Rab4A-directed endosome traffic shapes pro-inflammatory mitochondrial metabolism in T cells via mitophagy, CD98 expression, and kynurenine-sensitive mTOR activation

Nick Huang, Thomas Winans, Brandon Wyman, Zachary Oaks, Tamas Faludi, Gourav Choudhary, Zhi-Wei Lai, Joshua Lewis, Miguel Beckford, Manuel Duarte, Daniel Krakko, Akshay Patel, Joy Park, Tiffany Caza, Mahsa Sadeghzadeh, Laurence Morel, Mark Haas, Frank Middleton, Katalin Banki and Andras Perl ()
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Nick Huang: State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse
Thomas Winans: State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse
Brandon Wyman: State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse
Zachary Oaks: State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse
Tamas Faludi: State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse
Gourav Choudhary: State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse
Zhi-Wei Lai: State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse
Joshua Lewis: State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse
Miguel Beckford: State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse
Manuel Duarte: State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse
Daniel Krakko: State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse
Akshay Patel: State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse
Joy Park: State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse
Tiffany Caza: State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse
Mahsa Sadeghzadeh: State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse
Laurence Morel: University of Florida
Mark Haas: Cedars-Sinai Medical Center
Frank Middleton: State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse
Katalin Banki: State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse
Andras Perl: State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse

Nature Communications, 2024, vol. 15, issue 1, 1-26

Abstract: Abstract Activation of the mechanistic target of rapamycin (mTOR) is a key metabolic checkpoint of pro-inflammatory T-cell development that contributes to the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE), however, the underlying mechanisms remain poorly understood. Here, we identify a functional role for Rab4A-directed endosome traffic in CD98 receptor recycling, mTOR activation, and accumulation of mitochondria that connect metabolic pathways with immune cell lineage development and lupus pathogenesis. Based on integrated analyses of gene expression, receptor traffic, and stable isotope tracing of metabolic pathways, constitutively active Rab4AQ72L exerts cell type-specific control over metabolic networks, dominantly impacting CD98-dependent kynurenine production, mTOR activation, mitochondrial electron transport and flux through the tricarboxylic acid cycle and thus expands CD4+ and CD3+CD4−CD8− double-negative T cells over CD8+ T cells, enhancing B cell activation, plasma cell development, antinuclear and antiphospholipid autoantibody production, and glomerulonephritis in lupus-prone mice. Rab4A deletion in T cells and pharmacological mTOR blockade restrain CD98 expression, mitochondrial metabolism and lineage skewing and attenuate glomerulonephritis. This study identifies Rab4A-directed endosome traffic as a multilevel regulator of T cell lineage specification during lupus pathogenesis.

Date: 2024
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DOI: 10.1038/s41467-024-46441-2

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