The nutrient-sensing Rag-GTPase complex in B cells controls humoral immunity via TFEB/TFE3-dependent mitochondrial fitness

Xingxing Zhu, Yue Wu, Yanfeng Li, Xian Zhou, Jens O. Watzlawik, Yin Maggie Chen, Ariel L. Raybuck, Daniel D. Billadeau, Virginia Smith Shapiro, Wolfdieter Springer, Jie Sun, Mark R. Boothby and Hu Zeng ()
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Xingxing Zhu: Mayo Clinic Rochester
Yue Wu: University of Virginia
Yanfeng Li: Mayo Clinic Rochester
Xian Zhou: Mayo Clinic Rochester
Jens O. Watzlawik: Mayo Clinic
Yin Maggie Chen: Mayo Clinic Rochester
Ariel L. Raybuck: Vanderbilt University Medical Center and School of Medicine
Daniel D. Billadeau: Mayo Clinic Rochester
Virginia Smith Shapiro: Mayo Clinic Rochester
Wolfdieter Springer: Mayo Clinic
Jie Sun: University of Virginia
Mark R. Boothby: Vanderbilt University Medical Center and School of Medicine
Hu Zeng: Mayo Clinic Rochester

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Germinal center (GC) formation, which is an integrant part of humoral immunity, involves energy-consuming metabolic reprogramming. Rag-GTPases are known to signal amino acid availability to cellular pathways that regulate nutrient distribution such as the mechanistic target of rapamycin complex 1 (mTORC1) pathway and the transcription factors TFEB and TFE3. However, the contribution of these factors to humoral immunity remains undefined. Here, we show that B cell-intrinsic Rag-GTPases are critical for the development and activation of B cells. RagA/RagB deficient B cells fail to form GCs, produce antibodies, and to generate plasmablasts during both T-dependent (TD) and T-independent (TI) humoral immune responses. Deletion of RagA/RagB in GC B cells leads to abnormal dark zone (DZ) to light zone (LZ) ratio and reduced affinity maturation. Mechanistically, the Rag-GTPase complex constrains TFEB/TFE3 activity to prevent mitophagy dysregulation and maintain mitochondrial fitness in B cells, which are independent of canonical mTORC1 activation. TFEB/TFE3 deletion restores B cell development, GC formation in Peyer’s patches and TI humoral immunity, but not TD humoral immunity in the absence of Rag-GTPases. Collectively, our data establish the Rag GTPase-TFEB/TFE3 pathway as a likely mTORC1 independent mechanism to coordinating nutrient sensing and mitochondrial metabolism in B cells.

Date: 2024
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DOI: 10.1038/s41467-024-54344-5

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