Multiomic Analysis Reveals a Key BCAT1 Role in mTOR Activation by B Cell Receptor and TLR9

Authors

Rui Guo
Yizhe Sun
Matthew Y Lim
Hardik Shah
Joao A Paulo
Rahaman A Ahmed
Weixing Li
Yuchen Zhang
Haopeng Yang
Liang Wei Wang
Daniel Strebinger
Nicholas A Smith
Meng Li
Merrin Man Long Leong
Michael Lutchenkov
Jin Hua Liang
Zhixuan Li
Yin Wang
Rishi Puri
Ari Melnick
Michael R Green
John M Asara
Adonia E Papathanassiu
Duane R Wesemann
Steven P Gygi
Vamsi K Mootha
Benjamin E Gewurz

Publication Date

11-17-2025

Journal

Journal of Clinical Investigation

DOI

10.1172/JCI186258

PMID

40924473

PMCID

PMC12618069

PubMedCentral® Posted Date

9-9-2025

PubMedCentral® Full Text Version

Post-print

Abstract

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.

Keywords

Humans, Receptors, Antigen, B-Cell, Toll-Like Receptor 9, Animals, B-Lymphocytes, Mice, TOR Serine-Threonine Kinases, Transaminases, Lymphocyte Activation, Mechanistic Target of Rapamycin Complex 1, Signal Transduction, Cell biology, Metabolism, Adaptive immunity, Amino acid metabolism, Lymphomas

Published Open-Access

yes

Recommended Citation

Guo, Rui; Sun, Yizhe; Lim, Matthew Y; et al., "Multiomic Analysis Reveals a Key BCAT1 Role in mTOR Activation by B Cell Receptor and TLR9" (2025). Faculty, Staff and Student Publications. 5781.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5781