Selective autophagy of the adaptor protein Bcl10 modulates T cell receptor activation of NF-κB.
The 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.
Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD 20814, USA.
Suman
S
Paul
Anuj K
AK
Kashyap
Wei
W
Jia
You-Wen
YW
He
Brian C
BC
Schaefer
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071183:Autophagy-Related Proteins; D000074018:B-Cell CLL-Lymphoma 10 Protein; D020169:Caspases / Q000502:physiology; D002454:Cell Differentiation; D003600:Cytosol / Q000276:immunology / Q000648:ultrastructure; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D006360:Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D006706:Homeostasis; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000502:physiology; D010588:Phagosomes / Q000502:physiology / Q000648:ultrastructure; D025941:Protein Interaction Mapping; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000648:ultrastructure; D018418:Th2 Cells / Q000276:immunology / Q000648:ultrastructure; D044763:Ubiquitin-Conjugating Enzymes / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D000074018:B-Cell CLL-Lymphoma 10 Protein; C488088:Bcl10 protein, mouse; D006360:Heat-Shock Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D044763:Ubiquitin-Conjugating Enzymes; D020169:Caspases; C498509:Malt1 protein, mouse; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; C568853:Atg3 protein, mouse