Rag-GTPase-TFEB/TFE3 axis controls B cell mitochondrial fitness and humoral immunity independent of mTORC1
During the humoral immune response, B cells undergo rapid metabolic reprogramming with a high demand for nutrients, which are vital to sustain the formation of the germinal centers (GCs). Rag-GTPases sense amino acid availability to modulate the mechanistic target of rapamycin complex 1 (mTORC1) pathway and suppress transcription factor EB (TFEB) and transcription factor enhancer 3 (TFE3), members of the microphthalmia (MiT/TFE) family of HLH-leucine zipper transcription factors. However, how Rag-GTPases coordinate amino acid sensing, mTORC1 activation, and TFEB/TFE3 activity in 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 generate plasmablasts in 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 Rag-GTPase-TFEB/TFE3 axis as an mTORC1 independent mechanism to coordinating nutrient sensing and mitochondrial metabolism in B cells.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
Research square - (2024) vom: 29. März |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhu, Xingxing [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Revised 25.04.2024 published: Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.21203/rs.3.rs-3957355/v1 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM370751434 |
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| 100 | 1 | |a Zhu, Xingxing |e verfasserin |4 aut | |
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| 500 | |a published: Electronic | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a During the humoral immune response, B cells undergo rapid metabolic reprogramming with a high demand for nutrients, which are vital to sustain the formation of the germinal centers (GCs). Rag-GTPases sense amino acid availability to modulate the mechanistic target of rapamycin complex 1 (mTORC1) pathway and suppress transcription factor EB (TFEB) and transcription factor enhancer 3 (TFE3), members of the microphthalmia (MiT/TFE) family of HLH-leucine zipper transcription factors. However, how Rag-GTPases coordinate amino acid sensing, mTORC1 activation, and TFEB/TFE3 activity in 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 generate plasmablasts in 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 Rag-GTPase-TFEB/TFE3 axis as an mTORC1 independent mechanism to coordinating nutrient sensing and mitochondrial metabolism in B cells | ||
| 650 | 4 | |a Preprint | |
| 700 | 1 | |a Wu, Yue |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yanfeng |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Xian |e verfasserin |4 aut | |
| 700 | 1 | |a Watzlawik, Jens O |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Yin Maggie |e verfasserin |4 aut | |
| 700 | 1 | |a Raybuck, Ariel L |e verfasserin |4 aut | |
| 700 | 1 | |a Billadeau, Daniel |e verfasserin |4 aut | |
| 700 | 1 | |a Shapiro, Virginia |e verfasserin |4 aut | |
| 700 | 1 | |a Springer, Wolfdieter |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Boothby, Mark R |e verfasserin |4 aut | |
| 700 | 1 | |a Zeng, Hu |e verfasserin |4 aut | |
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