RNA binding protein Sam68 promotes germinal center reaction and IgG response through regulation of miR29

TL;DR

The RNA binding protein Sam68 helps B cells respond to immune challenges by regulating miR29, which affects CD40 signaling and germinal center reactions.

Contribution

This study reveals a novel role of Sam68 in B cell function through miR29-mediated regulation of CD40 signaling.

Findings

Sam68 knockout mice show impaired germinal center reactions and antibody responses.

Sam68 deficiency leads to increased miR29a/b expression, which represses Traf4, a key CD40 pathway component.

Reduced CD40 signaling in Sam68-deficient B cells explains their poor germinal center participation.

Abstract

The RNA binding protein Sam68 (Src associated during mitosis of 68 kDa) has recently been shown to be involved in DNA double strand break repair. In the course of development and immune response, B cells undergo physiological double strand breaks during V(D)J recombination and class switch recombination. Therefore, envisaging a crucial role of Sam68 in B cell development and function, we analyzed Sam68 complete knockout (KO) mice. Despite normal B cell development, these animals exhibit impaired germinal centre (GC) reactions and antibody responses. Using a competitive bone marrow chimera model, as well as adoptive B cell transfer model, we could demonstrate that Sam68 deficient B cells are less competent to participate in GC than WT B cells. This reduced competence is mainly attributed to impaired B cell-intrinsic CD40 signaling as Sam68 KO B cells are less responsive to CD40 stimulation in vitro. Sam68 deficient B cells up-regulate the expression of microRNA miR29a and b which in turn repress the expression of Tumor necrosis factor receptor-associated factor 4 (Traf4) gene, a downstream effector molecule of CD40 pathway. Thus, Sam68 mediated Traf4 regulation through miR29 plays an important role in CD40 signaling in B cells, hence in GC response.

The online version contains supplementary material available at 10.1007/s00018-026-06145-w.

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