The ubiquitin ligase Peli1 negatively regulates T cell activation and prevents autoimmunity

Mikyoung, C. , et al. Nat. Immunol. 12, 1002–1009 (2011)

Speaker: Chin Kun Tsai (蔡進焜)                                         Time: 13:00~14:00, Nov.23, 2011

Commentator: Dr. Cheng-Chan Lu (呂政展老師)               Place: Room 601

Abstract

Regulation of T cell activation is important for preventing autoimmunity. T cells tolerate self antigens by various mechanisms. Deletion or inactivation of autoreative T cells is in central tolerance. However, peripheral tolerance is regulated by extrinsic and instrinsic factors. Ubiquitination is a critical mechanism regulate T cells activation¹ , and it is the E3-ubiquitin ligases Peli1 mediates the NF_ƘB activation by ubiquitination via TLRs and IL-1R². However the role of Peli1 in T cell activation is unclear. The authors stimulated wild-type and peli1-deficient T cells with anti-CD3 and anti-CD28 antibodies, and Tcells activation and proliferation were compared. In their model, higher activation of T cells were shown in Peli1-deficient than in wild-type, and Peli1-deficient T cells are hard to be suppressed by T_reg cells or TGF-β. Moreover, Peli1-deficient mices develop spontaneous autoimmunity. These findings suggest that Peli1 acts as important regulator in T cell activation and homeostasis. Furthermore, the authors found the NF_ƘB are hyperactive in Peli1-deficienct T cells and c-Rel is crucial for T cell activation in NF_ƘB signaling pathway³. They discovered Peli1-deficienct T cells enhanced c-Rel activation and they utilized truncated the C-terminal RING domain Peli1 which does not catalyze ubiquitination to prove that Peli1 negatively regulate c-Rel activation by ubiquitinion of c-Rel. Finally, K48R and K63R ubiquitin mutant were tested to prove the ubiquitination of c-Rel through Peli1 ligase is depend on K48-linked ubiquitin chain. In conclusion, degradation of c-Rel mediated by peli1 negatively regulates NF_ƘB activation that preventing hyperactivation of T cells. Peli1 may provide a potential therapeutic target for T cell disorders.

References

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2.      Schauvliege, R. et al. Pellino proteins: novel players in TLR and IL-1R signalling. J. Cell Mol. Med. 11, 453–461 (2007).

3.      Maggirwar, S.B. et al. Regulation of the interleukin-2 CD28 responsive element by NF-ATp and various NF-κB/Rel transcription factors. Mol. Cell Biol. 17, 2605–2614 (1997).