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mTORC2-PKBα/Akt1 Serine 473 phosphorylation axis is essential for regulation of FOXP3 Stability by chemokine CCL3 in

Ling Chen1, Jinjin Wu, Eric Pier

  • 1Department of Dermatology, Daping Hospital, Third Military Medical University, Chongqing, China.

The Journal of Investigative Dermatology
|December 11, 2012
PubMed

Insights

Chemokine CCL3 links infections to psoriasis by affecting FOXP3+Tregs stability. High CCL3 degrades FOXP3, while low CCL3 enhances stability via specific signaling pathways, impacting psoriasis development.

Area of Science:

  • Immunology
  • Dermatology
  • Molecular Biology

Background:

  • Infections are linked to psoriasis outbreaks and exacerbations.
  • Impaired function of FOXP3+Tregs is observed in psoriasis patients.
  • The underlying mechanisms connecting infections, Treg dysfunction, and psoriasis remain unclear.

Purpose of the Study:

  • To investigate the role of chemokine CCL3 as a link between infections and FOXP3+Treg stability in psoriasis.
  • To elucidate the molecular mechanisms by which CCL3 influences FOXP3 stability in the psoriatic microenvironment.

Main Methods:

  • Measurement of serum CCL3 levels in psoriasis patients and correlation with FOXP3 levels in CD4+CD25+T cells.
  • In vitro experiments to assess the effect of varying CCL3 concentrations on FOXP3 stability.
  • Analysis of signaling pathways involved, including PKBα/Akt1, mTORC1, PKC, and mTORC2 components like Sin1.

Main Results:

  • Serum CCL3 levels, induced by infections like streptococcus, correlate with FOXP3 levels in psoriatic T cells.
  • CCL3 exhibits bidirectional concentration-dependent effects on FOXP3 stability.
  • High CCL3 promotes FOXP3 degradation via K48-ubiquitination, dependent on PKBα/Akt1 S473 phosphorylation.
  • Low CCL3 enhances FOXP3 stability by maintaining PKC and restricting PKB/Akt pathways, partly by inhibiting Sin1 nuclear translocation.

Conclusions:

  • CCL3 acts as a critical mediator between infections and FOXP3+Treg stability in psoriasis.
  • The CCL3-mediated regulation of FOXP3 stability involves complex signaling pathways, including PKBα/Akt1 phosphorylation and mTORC2.
  • Targeting the CCL3-Treg axis may offer novel therapeutic strategies for psoriasis.

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