{"doi":"10.1101/2024.02.26.582122","title":"The nutrient-sensing Rag-GTPase complex in B cells controls humoral immunity via TFEB/TFE3-dependent mitochondrial fitness","abstract":"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 pathway as an mTORC1 independent mechanism to coordinating nutrient sensing and mitochondrial metabolism in B cells.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":494804,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.948,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":256577,"name":"Yue Wu","orcid":"0000-0003-3667-2960","position":1,"is_corresponding":false},{"id":580633,"name":"Yanfeng Li","orcid":"0000-0003-3446-4252","position":2,"is_corresponding":false},{"id":514460,"name":"Xian Zhou","orcid":"0000-0001-8766-8158","position":3,"is_corresponding":false},{"id":314467,"name":"Jens O. Watzlawik","orcid":"0000-0003-0610-0267","position":4,"is_corresponding":false},{"id":1341168,"name":"Yin Chen","orcid":"0009-0002-6846-3012","position":5,"is_corresponding":false},{"id":655024,"name":"Ariel Raybuck","orcid":"0000-0003-3445-2112","position":6,"is_corresponding":false},{"id":290939,"name":"Daniel D. Billadeau","orcid":"0000-0002-2296-9547","position":7,"is_corresponding":false},{"id":404865,"name":"Virginia Smith Shapiro","orcid":"0000-0001-9978-341X","position":8,"is_corresponding":false},{"id":314474,"name":"Wolfdieter Springer","orcid":"0000-0002-1178-3149","position":9,"is_corresponding":false},{"id":254567,"name":"Jie Sun","orcid":"0000-0002-2347-4511","position":10,"is_corresponding":false},{"id":484605,"name":"Mark Boothby","orcid":"0000-0003-2593-8276","position":11,"is_corresponding":false},{"id":287643,"name":"Hu Zeng","orcid":"0000-0002-9909-7732","position":12,"is_corresponding":false},{"id":580632,"name":"Xingxing Zhu","orcid":"0000-0001-8411-319X","position":0,"is_corresponding":true}],"reference_count":74,"raw_metadata":null,"created_at":"2026-07-19T02:09:11.736910Z","pmid":"38463988","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}