{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T17:24:33Z","timestamp":1775323473881,"version":"3.50.1"},"posted":{"date-parts":[[2026,4,1]]},"group-title":"Immunology","reference-count":47,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH grants","award":["R01AI109020"],"award-info":[{"award-number":["R01AI109020"]}]},{"name":"NIH grants","award":["R01AI158353"],"award-info":[{"award-number":["R01AI158353"]}]},{"name":"NIH grants","award":["R21AI156243"],"award-info":[{"award-number":["R21AI156243"]}]},{"name":"University of Washington, Bridge Funding"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,1]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>\n                  B cell development relies on stringent checkpoints that ensure immune competence and eliminate autoreactive clones. Transitional B cells (B220\u207aCD93\u207a), 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 (\n                  <jats:italic>\n                    Fnip1\n                    <jats:sup>fl\/fl<\/jats:sup>\n                    CD21Cre\n                  <\/jats:italic>\n                  ), loss of Fnip1 results in a developmental arrest at the transitional B220\u207aCD93\n                  <jats:sup>mid<\/jats:sup>\n                  stage, severely limiting differentiation into FO and MZ B cells and leading to accumulation of a distinct enlarged CD19\n                  <jats:sup>high<\/jats:sup>\n                  , 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.\n                <\/jats:p>","DOI":"10.64898\/2026.03.30.715168","type":"posted-content","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T16:15:27Z","timestamp":1775060127000},"source":"Crossref","is-referenced-by-count":0,"title":["FNIP1 Modulates B Cell Receptor Signaling Strength by Coordinating Metabolism During Development"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6774-6515","authenticated-orcid":false,"given":"Heon","family":"Park","sequence":"first","affiliation":[{"name":"Department of Comparative Medicine, University of Washington, Seattle, Washington, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan","family":"Culbert","sequence":"additional","affiliation":[{"name":"Department of Comparative Medicine, University of Washington, Seattle, Washington, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dechen","family":"Sakya","sequence":"additional","affiliation":[{"name":"Department of Comparative Medicine, University of Washington, Seattle, Washington, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raynah R.","family":"Silprasert","sequence":"additional","affiliation":[{"name":"Department of Comparative Medicine, University of Washington, Seattle, Washington, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1903-7850","authenticated-orcid":false,"given":"Brian M.","family":"Iritani","sequence":"additional","affiliation":[{"name":"Department of Comparative Medicine, University of Washington, Seattle, Washington, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026040409150669000_2026.03.30.715168v1.1","doi-asserted-by":"crossref","unstructured":"Hardy, R. R. & Hayakawa, K. B cell development pathways. Annual Review of Immunology 19, (2001).","DOI":"10.1146\/annurev.immunol.19.1.595"},{"key":"2026040409150669000_2026.03.30.715168v1.2","doi-asserted-by":"crossref","unstructured":"Melchers, F . Anergic B Cells Caught in the Act. Immunity 25, (2006).","DOI":"10.1016\/j.immuni.2006.11.003"},{"key":"2026040409150669000_2026.03.30.715168v1.3","doi-asserted-by":"crossref","unstructured":"Tanaka, S. , Ise, W. , Baba, Y. & Kurosaki, T . Silencing and activating anergic B cells. Immunological Reviews 307, (2022).","DOI":"10.1111\/imr.13053"},{"key":"2026040409150669000_2026.03.30.715168v1.4","doi-asserted-by":"crossref","unstructured":"Cambier, J. C. , Gauld, S. B. , Merrell, K. T. & Vilen, B. J . B-cell anergy: From transgenic models to naturally occurring anergic B cells? 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Med. 212, (2015).","DOI":"10.1084\/jem.20150585"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.03.30.715168","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T16:15:25Z","timestamp":1775319325000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.03.30.715168"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,1]]},"references-count":47,"URL":"https:\/\/doi.org\/10.64898\/2026.03.30.715168","relation":{},"subject":[],"published":{"date-parts":[[2026,4,1]]},"subtype":"preprint"}}