A stimulating collaboration

signaling update home

SOURCE:

NGFI-A-binding protein 2 works as a co-activator of T-cell function by promoting the transcription of interleukin-2 mediated by the transcription factor early growth response 1 (EGR1).

The catalogue of molecules that are involved in activating or inhibiting T-cell function is ever increasing, and now another can be added to it. In a study published in The Journal of Immunology, NGFI-A-binding protein 2 (NAB2) is shown to function as a co-activator of T-cell function by promoting the transcription of interleukin-2 (IL2) mediated by the transcription factor early growth response 1 (EGR1).

NAB2 has no DNA-binding domain so it must collaborate with transcription factors to affect gene transcription. In this capacity, it has been shown to be both a co-activator and a co-repressor of EGR-mediated transcription. In T cells, expression of the EGR proteins EGR1, EGR2 and EGR3 is markedly upregulated after ligation of the T-cell receptor (TCR). EGR1 is known to stimulate T-cell activation and promote IL-2 production, whereas EGR2 and EGR3 have inhibitory effects on T cells. So, how does NAB2 influence EGR-mediated transcription in T cells?

Initial analysis of NAB2 expression revealed that the highest levels of NAB2 protein expression coincided with maximum IL2 transcription in T cells stimulated with CD3- and CD28-specific antibodies. This led the authors to suggest that NAB2 might have an activating role in T cells. Consistent with this hypothesis, overexpression of NAB2 increased the transcription of a reporter gene driven by the IL2 promoter. By contrast, knockdown of NAB2 expression using small interfering RNA led to a reduction in both proliferation and IL-2 production by Jurkat T cells activated by ligation of the TCR and the co-stimulatory molecule CD28. Finally, Jurkat T cells expressing a dominant-negative form of NAB2 that lacks the NCD2 domain responsible for interacting with EGR proteins inhibited the induction of IL2-promoter-driven transcription by NAB2.

The authors next asked whether the activating effect of NAB2 was mediated through EGR1, which is known to bind the IL2 promoter and promote IL2 transcription. By carrying out chromatin immunoprecipitation assays, they showed that after T-cell activation both NAB2 and EGR1 are recruited to the IL2 promoter. Importantly, the recruitment of both EGR1 and NAB1 was abrogated by mutation of the EGR1-binding site in the IL2 promoter, which confirms that NAB2 binds to the IL2 promoter by interacting with EGR1.

So, this study identifies NAB2 as a new TCR-induced transcriptional co-activator of IL-2 production.

Lucy Bird

References

Collins, S. et al. TCR-induced NAB2 enhances T cell function by coactivating IL-2 transcription. J. Immunol. 177, 8301–8305 (2006) | PubMed |