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Recent BCR stimulation induces a negative autoregulatory loop via FBXO10 mediated degradation of HGAL

Fengjie Guo1,2, Yuan Luo1,2, Xiaoyu Jiang1,2

  • 1Division of Hematology, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.

Leukemia
|October 2, 2019
PubMed

Insights

B-cell receptor (BCR) signaling is regulated by a novel mechanism involving FBXO10 E3 ligase targeting HGAL for degradation. This discovery reveals a new pathway for controlling immune responses and has implications for lymphoma.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Signaling

Background:

  • B-cell receptor (BCR) signaling is critical for adaptive immunity and tightly regulated.
  • Existing inhibitory mechanisms include co-receptor stimulation and ITIM phosphorylation.
  • A gap exists in understanding direct BCR stimulation-induced negative regulation.

Purpose of the Study:

  • To elucidate novel mechanisms regulating BCR signaling.
  • To investigate the role of SCF-FBXO10 ubiquitin E3 ligase in BCR signaling.
  • To define the function of the FBXO10-HGAL axis in immune regulation.

Main Methods:

  • Investigated the post-translational modification of SCF-FBXO10 upon BCR stimulation.
  • Utilized ubiquitylation assays to identify FBXO10 targets.
  • Assessed the impact of FBXO10-HGAL interaction on BCR signaling components (calcium influx, phosphorylation).

Main Results:

  • BCR stimulation induces rapid, reversible palmitoylation and cell membrane relocalization of SCF-FBXO10.
  • SCF-FBXO10 targets HGAL for ubiquitylation and degradation, independent of HGAL phosphorylation.
  • FBXO10-mediated HGAL degradation reduces BCR-induced calcium influx and proximal effector phosphorylation.

Conclusions:

  • Direct BCR stimulation can negatively regulate BCR signaling via the FBXO10-HGAL axis.
  • This pathway represents a novel mechanism for controlling B-cell immune responses.
  • Dysregulation of the FBXO10-HGAL axis may contribute to lymphomagenesis, particularly in DLBCL.

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