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

• Published in: Nature communications Vol. 15; no. 1; pp. 2598 - 26
• Main Authors: Huang, Nick, Winans, Thomas, Wyman, Brandon, Oaks, Zachary, Faludi, Tamas, Choudhary, Gourav, Lai, Zhi-Wei, Lewis, Joshua, Beckford, Miguel, Duarte, Manuel, Krakko, Daniel, Patel, Akshay, Park, Joy, Caza, Tiffany, Sadeghzadeh, Mahsa, Morel, Laurence, Haas, Mark, Middleton, Frank, Banki, Katalin, Perl, Andras
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.03.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 14; 38; 631/250/1619/40; 631/250/1619/554; 631/250/2152/1566/1618; 631/250/38; 692/4023/1670; 82/29; Animals; Autoantibodies; Autoimmune diseases; Autoimmunity; CD3 antigen; CD4 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - metabolism; Cell activation; Cell lineage; Chronic conditions; Clonal deletion; Electron transport; Endosomes; Endosomes - metabolism; Gene expression; Glomerulonephritis; Glomerulonephritis - metabolism; Humanities and Social Sciences; Immune system; Inflammation; Kynurenine - metabolism; Lupus; Lupus Erythematosus, Systemic; Lymphocytes; Lymphocytes T; Metabolic networks; Metabolic pathways; Metabolism; Mice; Mitochondria; Mitochondria - metabolism; Mitophagy; multidisciplinary; Pathogenesis; Protein transport; Protein turnover; rab4 GTP-Binding Proteins - metabolism; Rapamycin; Receptors; Science; Science (multidisciplinary); Stable isotopes; Systemic lupus erythematosus; TOR protein; TOR Serine-Threonine Kinases - metabolism; Tricarboxylic acid cycle
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-46441-2

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 Rab4A Q72L 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. Activation of the mechanistic target of rapamycin (mTOR) is important in the metabolic function of proinflammatory T cells in autoimmunity. Here the authors characterise how Rab4A is involved with CD98 and endosome recycling which subsequently affects mTOR activation, autoimmunity and T cell expansion.