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bioRxiv · 10.64898/2026.03.30.715168

FNIP1 Modulates B Cell Receptor Signaling Strength by Coordinating Metabolism During Development.

Park, H.·Culbert, R.·Sakya, D.·Silprasert, R. R.·Iritani, B. M.
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Abstract

B cell development relies on stringent checkpoints that ensure immune competence and eliminate autoreactive clones. Transitional B cells (B220CD93), which emerge from the bone marrow, migrate to the spleen and differentiate into follicular (FO) or marginal zone (MZ) B cells, a process governed by B cell receptor (BCR) signaling strength, metabolic fitness, and survival cues. Here, we identify Folliculin Interacting Protein 1 (Fnip1) as a key regulator of this developmental transition. Using conditional Fnip1-deficient mice (Fnip1fl/flCD21Cre), loss of Fnip1 results in a developmental arrest at the transitional B220CD93mid stage, severely limiting differentiation into FO and MZ B cells and leading to accumulation of a distinct enlarged CD19high, RAG negative B cells. Fnip1 modulates BCR signaling thresholds and metabolic programming by regulating the AMPK/FLCN/TFEB and CD19/PI3K/Akt/mTORC1 pathways through restricting TFEB access to the nucleus. Using the MD4/mHEL/sHEL tolerance model, we show that Fnip1 is dispensable for negative selection but is essential for maintaining peripheral tolerance. Together, our findings define Fnip1 as a metabolic gatekeeper that integrates nutrient-sensing pathways with BCR signaling to orchestrate transitional B cell fate decisions, promote peripheral tolerance, and maintain immune homeostasis.

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Park, H., Culbert, R., Sakya, D., Silprasert, R. R., Iritani, B. M.. 2026-04-01. FNIP1 Modulates B Cell Receptor Signaling Strength by Coordinating Metabolism During Development.. https://doi.org/10.64898/2026.03.30.715168

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