# Fibrinogen‐Like Protein 2 Modulates B Cell Mucosal Immunity by Suppressing Receptor for Activated C‐Kinase 1‐Mediated AKT Phosphorylation

## TL;DR

This study reveals how Fibrinogen-Like Protein 2 regulates B cell function and mucosal immunity by inhibiting key signaling pathways.

## Contribution

The paper identifies a novel role for Fgl2 in modulating BCR signaling and B cell differentiation through its interaction with Rack1.

## Key findings

- Fgl2 deficiency increases B cell activation and differentiation into IgA+ plasma cells.
- Fgl2 interacts with Rack1 to suppress AKT phosphorylation and BCR signaling.
- Rack1 inhibition counteracts the effects of Fgl2 deficiency in B cells.

## Abstract

Fibrinogen‐like protein 2 (Fgl2) is a critical immunoregulatory factor, yet its precise roles in B‐cell biology and mucosal immunity remain largely undefined. In this study, utilizing Fgl2‐knockout (KO) mice, we identified novel B cell subsets in the spleen (SPL), predominantly characterized by IGHA clonal dominance. Employing an intestinal Trichinella spiralis (T. s) infection model and samples from patients exhibiting mucosal immune responses (the early stage of COVID‐19 infection), we investigated the function of Fgl2 in mucosal immunity. We demonstrate that Fgl2 directly interacts with Receptor for activated C‐kinase 1 (Rack1), thereby attenuating B cell receptor (BCR) signaling and metabolic activity by inhibiting AKT phosphorylation. Furthermore, the Fgl2 deficiency‐induced expansion of marginal zone (MZ) B cells, germinal center (GC) B cells, and IgA+ plasma cells was effectively counteracted by in vivo Rack1 inhibition. Consistently, a Rack1 inhibitor also abrogated the enhanced activation of Fgl2‐deficient B cells in vitro. Fgl2 deficiency also augmented early B cell activation, including B cell spreading, clustering, and signalosome recruitment, through upregulation of the DOCK8‐WASP‐actin axis. Our research uncovers an intrinsic role for Fgl2 in regulating BCR signaling, B cell differentiation, and mucosal immunity, elucidating a key underlying molecular mechanism.

In our study, B cells are activated with the assistance of Breg and Tfh cells, subsequently differentiating into IgA+ plasma cells. These plasma cells produce secretory IgA (sIgA) at mucosal surfaces to combat viral and parasitic infections. Mechanistically, Fgl2 directly binds to Rack1. This interaction influences B‐cell metabolism by inhibiting AKT phosphorylation. Concurrently, it also impacts B‐cell activation by attenuating B‐cell receptor (BCR) signaling, including critical early events such as B‐cell spreading, clustering, and signalosome recruitment.