# Cbl promotes MyD88 ubiquitin-mediated degradation in macrophages via phosphorylation and calcium mobilization

## TL;DR

The study shows that Cbl suppresses inflammation by promoting the degradation of MyD88 in macrophages through ubiquitination.

## Contribution

Cbl is identified as a novel E3 ligase that directly regulates MyD88 stability via phosphorylation and calcium signaling.

## Key findings

- Cbl interacts with and promotes ubiquitination of MyD88 in macrophages.
- Cbl deficiency increases cytokine production and MyD88-dependent signaling.
- Cbl activity requires calcium and phosphorylation for MyD88 downregulation.

## Abstract

Precise regulation of Toll-like receptor (TLR) signaling via myeloid differentiation factor 88 (MyD88) is critical for balancing immune defense and inflammation. While ubiquitination represents a dominant mechanism controlling MyD88 stability, the full spectrum of E3 ligases that regulate MyD88 stability remains undefined.

In the present study, we investigated the regulatory role of Cbl in MyD88 signaling in macrophage.

We identified Cbl as a direct negative regulator of MyD88 in macrophages. Cbl is upregulated during inflammatory responses, and myeloid-specific Cbl deficiency exacerbates cytokine production and MyD88-dependent signaling in macrophages. Mechanistically, Cbl could interact with MyD88. The overexpression of Cbl promoted the ubiquitination and proteasomal degradation of MyD88, whereas Cbl deficiency abrogated its ubiquitination. Moreover, we found that Cbl activation required intracellular calcium and phosphorylation. Calcium chelation and inhibited phosphorylation of Cbl abrogated Cbl-mediated MyD88 downregulation.

findings establish Cbl as a novel suppressor of inflammation and direct-interacting E3 ligase of MyD88 in macrophages. Our study expands the knowledge of intrinsic immunoregulatory networks of TLR– MyD88 signaling and the regulatory mechanism of Cbl, suggesting new therapeutic strategies for inflammatory disorders.