Selective Autophagy of the Adaptor Protein Bcl10 Modulates T Cell Receptor Activation of NF-κB

SummaryThe adaptor protein Bcl10 is a critically important mediator of T cell receptor (TCR)-to-NF-κB signaling. Bcl10 degradation is a poorly understood biological phenomenon suggested to reduce TCR activation of NF-κB. Here we have shown that TCR engagement triggers the degradation of Bcl10 in primary effector T cells but not in naive T cells. TCR engagement promoted K63 polyubiquitination of Bcl10, causing Bcl10 association with the autophagy adaptor p62. Paradoxically, p62 binding was required for both Bcl10 signaling to NF-κB and gradual degradation of Bcl10 by autophagy. Bcl10 autophagy was highly selective, as shown by the fact that it spared Malt1, a direct Bcl10 binding partner. Blockade of Bcl10 autophagy enhanced TCR activation of NF-κB. Together, these data demonstrate that selective autophagy of Bcl10 is a pathway-intrinsic homeostatic mechanism that modulates TCR signaling to NF-κB in effector T cells. This homeostatic process may protect T cells from adverse consequences of unrestrained NF-κB activation, such as cellular senescence.

Graphical AbstractFigure optionsDownload high-quality image (191 K)Download as PowerPoint slideHighlights
► TCR-dependent Bcl10 degradation occurs in effector T cells but not naive T cells
► Bcl10 is degraded via TCR-dependent selective autophagy
► p62 is a key mediator of NF-κB activation and Bcl10 autophagy
► Selective autophagy of Bcl10 limits TCR activation of NF-κB