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Regulation of TCR Signaling to NF-kB

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Technical Report

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Uniformed Services University Of The Health Sciences Bethesda United States

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T cells play an important role in the adaptive immune response to invading pathogens. Pathogen derived antigenic peptides in combination with MHC molecules are recognized by the T cell receptor TCR. Antigen-specific binding initiates signaling cascades in the T cell cytosol that ultimately culminate in the activation of several key transcription factors. One such transcription factor is NF-B, which controls expression of genesrequired for T cell activation, proliferation and gain of effector function. The signalingproteins Bcl10 and Malt1 are required for successful transmission of the activation signal from the TCR to NF-B. Previous observations demonstrated that antigen mediated TCR stimulation leads to formation of Bcl10 and Malt1 cytosolic aggregates, which were named POLKADOTS. Using primary effector T cells and D10 CD4 T cell clones, we demonstrate that the TCR-to-NF-B activation signal is both transmitted by and terminated at the POLKADOTS signalosome. We show that POLKADOTS formation depends on binding of K63-polyubiquitinated Bcl10 to cytosolic p62 clusters, and that these clusters are the sites of IKK and IB phosphorylation, two critical steps required for NF-B activation. Additionally, we demonstrate that in response to TCR stimulation, a significant fraction of K63-polyubiquitinated Bcl10 within the POLKADOTS isselectively taken up and degraded by autophagolysosomes. This degradation reduces the amount of actively signaling Bcl10 molecules available for signal transmission, which ultimately limits the degree of NF-B activation. Thus by both providing a platform for transmission of the activation signal and by degrading the crucial signaling protein Bcl10, POLKADOTS serve as an important cytosolic signal integration site for the TCR-to-NF-B cascade.

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