SFB 1054 Seminar - Taku Kureha

Title: The CCR4-NOT complex contributes to survival of DP thymocytes during positive selection by reducing ASK1 translation

Positive selection of double-positive (DP) thymocytes requires precise regulations of T-cell antigen receptor (TCR) signaling. We here describe that limitation of mRNA poly (A) tail length by the deadenylase CCR4-NOT complex ensures the positive selection by modulating TCR signaling. The CCR4-NOT complex is the major deadenylase that removes poly(A) tails from mRNAs. Recently, we found that the number of mature T cells was reduced in mice hetero-deficient for CNOT3, a subunit of the CCR4-NOT complex. The data suggest an involvement of CNOT3 in T cell development and/or maintenance. To clarify the role of CNOT3 in T cell, we generated mice devoid of CNOT3 in T cell specific manner (Cnot3f/f Cd4-Cre mice). T cell-specific depletion of the CNOT3 subunit revealed requirements of the CCR4-NOT complex in the positive selection and inhibition of inappropriate Jnk and p38 activations induced by TCR stimulation. We found the survival defect occurred in the presence of TCR stimulation. These results indicated that the defect of DP differentiation in Cnot3f/f Cd4-Cre mice was caused by the cell death after TCR stimulation. Furthermore, we found that the CCR4-NOT complex post-transcriptionally attenuates expression of ASK1, thereby preventing inappropriate activation of Jnk and p38 after TCR stimulation, which leads TCR-induced cell death of DP thymocytes. The CCR4-NOT complex shorten poly (A) tail of Ask1 mRNA through the recognition of its 3’ non-coding region via interaction with Cpeb4 protein, thereby down-regulating ASK1 protein. Consequently, our data suggest a novel link between the deadenylase-mediated poly(A) tail shortening and the T cell repertoire formation.

Venue: 

BioMedical Center (BMC), Room N 01.017,
Großhaderner Str. 9, Planegg-Martinsried

Host: Vigo Heissmeyer (A03)