PDK1 Nucleates T Cell Receptor-Induced Signaling Complex for NF-κB Activation

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Abstract
Activation of the transcription factor NF-κB 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 θ (PKCθ), 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 IκB 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 PKCθ and through signal-dependent recruiting of both PKCθ and CARD11 to lipid rafts. PDK1-associated PKCθ 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-κB essential modifier). Hence, PDK1 plays a critical role by nucleating the TCR-induced NF-κB activation pathway in T cells.