Selective autophagy of Bcl10 modulates T cell receptor activation of NF-κB (121.16)

Abstract The adaptor protein Bcl10 is a critically important mediator of T cell receptor (TCR)-to-NF-κB signaling. Bcl10 can be degraded by TCR-dependent proteolysis, but the molecular mechanism of degradation is poorly understood. We show that TCR engagement triggers the degradation of Bcl10 in primary effector T cells, but not in naïve T cells. TCR engagement promotes K63-polyubiquitination of Bcl10, causing Bcl10 and its signaling partner Malt1 to associate with the autophagy adaptor protein, p62. Confocal microscopy shows that cytosolic aggregates of Bcl10, Malt1, and p62 also co-localize with the autophagosome membrane protein, LC3. Biochemical analysis shows that LC3 co-precipitates in a TCR-dependent manner with Bcl10 and p62, but not with Malt1. Inhibition of autophagosome formation prevents Bcl10 degradation, leading to long-term association between Bcl10 and Malt1. Thus, the physical separation of Bcl10 and Malt1 is a direct consequence of Bcl10 autophagy, and the autophagy of Bcl10 is a highly selective process. Finally we show that inhibition of Bcl10 autophagy enhances TCR activation of NF-κB. Together, these data demonstrate that selective autophagy of Bcl10 is a homeostatic mechanism that modulates TCR signaling to NF-κB in effector T cells. To our knowledge, our data represent the first example of selective autophagy as an intrinsic homeostatic mechanism modulating a signaling cascade.