PDK1 nucleates T cell receptor-induced signaling complex for NF-κB activation

Activation of the transcription factor NF-kappa B after engagement of the T cell receptor (TCR) is important for T cell proliferation and activation during the adaptive immune response. Recent reports have elucidated a signaling pathway that involves the protein kinase C theta (PKC theta), the scaffold protein CARD11 (also called CARMA-1), the caspase recruitment domain (CARD)-containing protein Bcl10, and the paracaspase (protease related to caspases) MALT1 as critical intermediates linking the TCR to the I kappa B kinase (IKK) complex. However, the events proximal to the TCR that initiate the activation of this signaling pathway remain poorly defined. We demonstrate that 3-phosphoinositide-dependent kinase 1 (PDK1) has an essential role in this pathway by regulating the activation of PKC theta and through signal-dependent recruiting of both PKC theta and CARD11 to lipid rafts. PDK1-associated PKC theta recruits the IKK complex, whereas PDK1-associated CARD11 recruits the Bcl10-MALT1 complex, thereby allowing activation of the IKK complex through Bcl10-MALT1-dependent ubiquitination of the IKK complex subunit known as NEMO (NF-kappa B essential modifier). Hence, PDK1 plays a critical role by nucleating the TCR-induced NF-kappa B activation pathway in T cells.