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14-3-3ζ suppresses RANKL signaling by destabilizing TRAF6.

R Ayyasamy1, S Fan2, P Czernik3

  • 1Department of Physiology & Pharmacology, College of Medicine & Life Sciences, University of Toledo, Toledo, Ohio, USA.

The Journal of Biological Chemistry
|June 22, 2024
PubMed
Summary
This summary is machine-generated.

14-3-3ζ protein suppresses bone loss by regulating TRAF6 levels, dampening inflammatory receptor activator of nuclear factor-κβ ligand (RANKL) signaling and osteoclast activity. This study reveals a novel mechanism in bone remodeling.

Keywords:
14-3-3ζRANKLTRAF6YWHAZbone homeostasismacrophagesosteoclastprotein degradationubiquitin

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Area of Science:

  • Cell Biology
  • Immunology
  • Bone Biology

Background:

  • Macrophages are key regulators of inflammation and bone loss.
  • Receptor activator of nuclear factor-κβ ligand (RANKL) drives osteoclast differentiation and bone resorption.
  • 14-3-3ζ's role in RANKL signaling and bone remodeling was previously unknown.

Purpose of the Study:

  • To investigate the function of 14-3-3ζ in regulating RANKL signaling and osteoclast activity.
  • To elucidate the molecular mechanism by which 14-3-3ζ influences osteoclastogenesis.

Main Methods:

  • Utilized 14-3-3ζ-deficient primary bone marrow-derived macrophages and RAW264.7 cells.
  • Assessed osteoclast differentiation, bone resorption, and signaling pathway activation (MAPK, AKT, NFATC1, p65) upon RANKL stimulation.
  • Investigated protein-protein interactions (14-3-3ζ-TRAF6, RANK-TRAF6) and TRAF6 ubiquitination/degradation.

Main Results:

  • 14-3-3ζ deficiency enhanced osteoclast formation and bone resorption activity.
  • 14-3-3ζ suppressed RANKL-induced MAPK/AKT phosphorylation and transcription factor nuclear translocation.
  • 14-3-3ζ interacted with TRAF6, promoting its ubiquitination and degradation, thereby inhibiting RANKL signaling.

Conclusions:

  • 14-3-3ζ acts as a negative regulator of RANKL signaling by controlling TRAF6 stability.
  • 14-3-3ζ dampens osteoclast activity and bone resorption.
  • This study identifies a novel role for 14-3-3ζ in regulating bone remodeling and inflammation.