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bioRxiv · 10.64898/2026.08.06.743158

OTUB1 controls marginal zone B-cell development by stabilizing RelA in a CD40-dependent manner

Vogt, J. F.·Tang, Y.·Reissig, S.·Karantanou, C.·Kumar, S.·Stylianakis, E.·Schlueter, D.·Waisman, A.·Hoevelmeyer, N.
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Abstract

Ubiquitin-dependent regulation of NF-{kappa}B signaling is essential for B-cell homeostasis and fate decisions, yet the contribution of specific deubiquitinating enzymes remains incompletely defined. OTUB1, a lysine-48-specific deubiquitinase, has been broadly implicated in immune regulation, including control of NF-{kappa}B signaling and prevention of immune hyperactivation. Previous studies have demonstrated that B cell-specific deletion of OTUB1 leads to B cell hyperplasia, increased antibody production, and lupus-like autoimmunity, highlighting its importance in maintaining B cell tolerance and immune homeostasis. Using B cell-specific OTUB1-deficient mice, we show that loss of OTUB1 leads to a marked expansion of marginal zone (MZ) B cells and their precursor populations in the spleen, accompanied by an activated phenotype and enhanced proliferative responses, particularly upon CD40 stimulation. OTUB1 deficiency results in altered CD40-induced NF-{kappa}B signaling, characterized by enhanced I{kappa}B degradation and increased nuclear accumulation of p50-containing NF-{kappa}B complexes, despite reduced RelA stability. Mechanistically, we show that OTUB1 interacts with RelA, restricting its lysine-48-linked ubiquitination and proteasomal degradation, thereby stabilizing this key transcription factor. Collectively, these findings identify RelA as a novel OTUB1 target and uncover an additional layer of ubiquitin-dependent control of NF-{kappa}B signaling that governs splenic B-cell homeostasis and marginal zone B-cell development.

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Vogt, J. F., Tang, Y., Reissig, S., Karantanou, C., Kumar, S., Stylianakis, E., Schlueter, D., Waisman, A., Hoevelmeyer, N.. 2026-08-10. OTUB1 controls marginal zone B-cell development by stabilizing RelA in a CD40-dependent manner. https://doi.org/10.64898/2026.08.06.743158

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