Multiomic analysis reveals a key BCAT1 role in mTOR activation by B cell receptor and TLR9
B lymphocytes play major adaptive immune roles, producing antibodies and driving T cell responses. However, how immunometabolism networks support B cell activation and differentiation in response to distinct receptor stimuli remains incompletely understood. To gain insights, we systematically investigated acute primary human B cell transcriptional, translational, and metabolomic responses to B cell receptor (BCR), TLR9, CD40-ligand (CD40L), IL-4, or combinations thereof. T cell-independent BCR/TLR9 costimulation, which drives malignant and autoimmune B cell states, highly induced transaminase branched chain amino acid transaminase 1 (BCAT1), which localized to lysosomal membranes to support branched chain amino acid synthesis and mTORC1 activation. BCAT1 inhibition blunted BCR/TLR9, but not CD40L/IL-4-triggered B cell proliferation, IL-10 expression, and BCR/TLR pathway-driven lymphoma xenograft outgrowth. These results provide a valuable resource, reveal receptor-mediated immunometabolism remodeling to support key B cell phenotypes, and identify BCAT1 as an activated B cell therapeutic target.
Authors
- Daniel Strebinger (ORCID: https://orcid.org/0000-0001-8732-6414)
- Rui Guo (ORCID: https://orcid.org/0000-0001-7417-7018)
- Nicholas A. Smith (ORCID: https://orcid.org/0000-0001-8894-4249)
- Michael Lutchenkov
- Ari Melnick (ORCID: https://orcid.org/0000-0002-8074-2287)
- Haopeng Yang (ORCID: https://orcid.org/0000-0002-3870-2679)
- Yizhe Sun (ORCID: https://orcid.org/0000-0002-5986-3826)
- Duane R. Wesemann (ORCID: https://orcid.org/0000-0002-6690-944X)
- R.G. Ahmed (ORCID: https://orcid.org/0000-0002-9926-0624)
- John M. Asara (ORCID: https://orcid.org/0000-0001-7450-2589)
- Yin Wang (ORCID: https://orcid.org/0000-0002-8137-7496)
- Adonia E. Papathanassiu
- Meng Li (ORCID: https://orcid.org/0000-0002-6184-8887)
- Hardik Shah (ORCID: https://orcid.org/0000-0001-8408-5686)
- Merrin Man‐Long Leong (ORCID: https://orcid.org/0000-0003-4753-2285)
- Liang Wei Wang (ORCID: https://orcid.org/0000-0002-0324-8744)
- Michael Richard Green (ORCID: https://orcid.org/0000-0001-6309-9472)
- Vamsi Krishna Mootha (ORCID: https://orcid.org/0000-0001-9924-642X)
- Benjamin E. Gewurz (ORCID: https://orcid.org/0000-0002-3965-3418)
- Steven P. Gygi (ORCID: https://orcid.org/0000-0001-7626-0034)
- Matthew Lim (ORCID: https://orcid.org/0000-0001-7347-8409)
- Rishi Puri (ORCID: https://orcid.org/0000-0001-8849-7426)
- Weixing Li (ORCID: https://orcid.org/0000-0002-1697-7444)
- Yuchen Zhang (ORCID: https://orcid.org/0000-0001-8944-5230)
- Zhi‐Xuan Li (ORCID: https://orcid.org/0000-0002-8590-875X)
- Jin‐Hua Liang
- Joao A Paulo
Institutions
- Broad Institute (US)
- Boston University (US)
- Brigham and Women's Hospital (US)
- Beth Israel Deaconess Medical Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- Cornell University (US)
- Ragon Institute of MGH, MIT and Harvard (US)
- Massachusetts General Hospital (US)
- Dana-Farber/Harvard Cancer Center (US)
- Massachusetts Institute of Technology (US)
- Ergon Energy (Australia) (AU)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-09-09
- DOI
- https://doi.org/10.1172/jci186258
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Science Foundation
- Agency for Science, Technology and Research
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- National Institutes of Health
- Biomedical Research Council