Role of Ets‐1 phosphorylation in the effector function of Th cells

Abstract

The transcription factor Ets-1 critically regulates differentiation and function of T helper (Th) cells. In vitro studies have demonstrated that DNA binding and transcriptional activity of Ets-1 are regulated by phosphorylation. Depending on the site of phosphorylation, Ets-1 function can either be increased or inhibited. In addition, a splice variant lacking several inhibitory phosphorylation sites has been identified, raising the possibility that this splice variant may function differently from the full-length Ets-1. However, it is unclear how the activating and inhibitory phosphorylation events of Ets-1 are coordinated during Th cell activation. Furthermore, the biological consequences of Ets-1 phosphorylation and alternative splicing in regulating the function of Th cells are unknown. We report here that both activating and inhibitory phosphorylation events of Ets-1 occur simultaneously and independently of each other during Th cell activation. We further demonstrate that the effect of Ets-1 phosphorylation is very modest and that full-length Ets-1 and its splice variant are functionally interchangeable in the regulation of cytokine production in Th cells.

IL-10 transcription is negatively regulated by BAF180, a component of the SWI/SNF chromatin remodeling enzyme

“…Whether or not Stat6 is mediating the recruitment of SWI/SNF to the IL-10 locus or if Stat6 preferentially interacts with BAF or PBAF complexes remains to be determined. Ets-1 is reported to be a repressor of IL-10 expression [78,79], and Ets sequence motifs are enriched at BRG1 binding sites in resting Th cells [47]. …”

Tenuous paths in unexplored territory: From T cell receptor signaling to effector gene expression during thymocyte selection

“…NFAT or NF-κB, there is detailed connection to TCR signals, but little if any information about potential targets in thymocytes undergoing selection. Reciprocally, there is information on the biological function and molecular targets of Runx1 or Ets1, but their connection to TCR signaling pathways remains somewhat tenuous [20,37,70,71,103]. The following three examples illustrate emerging connections and remaining unexplored territory between sensing and effector circuitries; they underscore the scope of the challenges we face in building a dynamic transcriptional network of thymocyte selection.…”

Protective Role of Ets1 in SLE

“…Phosphorylation of Ets-1 can enhance or attenuate its transcriptional activity (54)(55)(56). However, neither activating nor inhibitory phosphorylation of Ets-1 had much impact on Th cytokine production (57). Acetylation of Ets-1 often results in the upregulation of target gene expression because acetylated Ets-1 is preferentially associated with the p300/CREB binding protein complexes (58).…”