FNIP1 Modulates B Cell Receptor Signaling Strength by Coordinating Metabolism During Development
Year: 2026
Type: preprint
Abstract: SUMMARY B cell development relies on stringent checkpoints that ensure immune competence and eliminate autoreactive clones. Transitional B cells (B220⁺CD93⁺), 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 ( Fnip1 fl/fl CD21Cre ), loss of Fnip1 results in a developmental arrest at the transitional B220⁺CD93 mid stage, severely limiting differentiation into FO and MZ B cells and leading to accumulation of a distinct enlarged CD19 high , 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.
Authors: Heon Park, Ryan Culbert, Dechen Sakya, Raynah R. Silprasert, Brian M. Iritani
Institution: University of Washington
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7147304045
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