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Inhibition of Ubc13-mediated Ubiquitination by GPS2 Regulates Multiple Stages of B Cell Development

Claudia Lentucci1, Anna C Belkina2,3, Carly T Cederquist1

  • 1From the Departments of Biochemistry.

The Journal of Biological Chemistry
|January 1, 2017
PubMed

Insights

G-protein Pathway Suppressor 2 (GPS2) restricts immune cell signaling by inhibiting Ubc13. GPS2 is essential for B cell development and homeostasis, as demonstrated by targeted deletion studies.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • Non-proteolytic ubiquitin signaling, particularly Lys63-linked chains, is crucial for immune cell function.
  • G-protein Pathway Suppressor 2 (GPS2) was previously identified as a regulator of TNFα signaling and lipid metabolism via Lys63 ubiquitination.

Purpose of the Study:

  • To elucidate the full extent of GPS2-mediated regulation of ubiquitination and its molecular mechanisms.
  • To investigate the role of GPS2 in immune cell signaling pathways.

Main Methods:

  • Direct inhibition assays of Ubc13 enzymatic activity by GPS2.
  • Analysis of TLR and BCR signaling pathways in immune cells.
  • Investigation of the AKT/FOXO1 pathway.
  • Generation of B cell-specific GPS2 knockout mouse models.

Main Results:

  • GPS2 directly inhibits Ubc13 enzymatic activity, restricting TLR and BCR signaling pathways.
  • GPS2 also regulates the AKT/FOXO1 pathway in immune cells.
  • B cell-specific deletion of GPS2 leads to developmental defects in B cell differentiation.

Conclusions:

  • GPS2 acts as a critical negative regulator of immune cell signaling pathways.
  • GPS2 plays essential roles in B cell development and homeostasis through both genomic and non-genomic functions.
Keywords:
Notch pathwaydevelopmenttoll-like receptor (TLR)ubiquitinubiquitin-conjugating enzyme (E2 enzyme)

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