Cell permeable inhibitors of the scaffold protein plenty of SH3 domains (POSH) or Sh3Rfl

Abstract

Here, we identify Plenty of SH3 (POSH) and JNK-interacting protein 1 (JIP-1) as a multi-protein scaffold network for TCR-mediated JNK1 activation in CD8+ T-cells. Disruption of the POSH/JIP-1 complex led to profound defects in the activation of JNK1, as well as deficient activation or induction of the transcription factors c-Jun, T-bet and Eomesodermin. Furthermore, disruption of the POSH/JIP complex in CD8+ T-cells resulted in impaired proliferation, decreased cytokine expression and the inability to control tumors. Collectively, these data identify a mechanism for the specific regulation of TCR-dependent JNK1 activation and function that is key for CD8+ T-cell responses. A group of compounds are described that individually or in concert target a common set of biological pathways important in T cell function, activation of innate inflammation, ischemic reperfusion injury, HIV release and oncogenesis.

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