Selective autophagy of the adaptor protein Bcl10 modulates T cell receptor activation of NF-κB

Immunity. 2012 Jun 29;36(6):947-58. doi: 10.1016/j.immuni.2012.04.008. Epub 2012 May 31.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / biosynthesis
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / physiology*
  • Animals
  • Autophagy / physiology*
  • Autophagy-Related Proteins
  • B-Cell CLL-Lymphoma 10 Protein
  • Caspases / physiology
  • Cell Differentiation
  • Cytosol / immunology
  • Cytosol / ultrastructure
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / immunology
  • Heat-Shock Proteins / biosynthesis
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / physiology
  • Homeostasis
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Confocal
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
  • NF-kappa B / metabolism*
  • Neoplasm Proteins / physiology
  • Phagosomes / physiology
  • Phagosomes / ultrastructure
  • Protein Interaction Mapping
  • Receptors, Antigen, T-Cell / immunology*
  • Sequestosome-1 Protein
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / ultrastructure
  • Th2 Cells / immunology
  • Th2 Cells / ultrastructure
  • Ubiquitin-Conjugating Enzymes / physiology

Substances

  • Adaptor Proteins, Signal Transducing
  • Autophagy-Related Proteins
  • B-Cell CLL-Lymphoma 10 Protein
  • Bcl10 protein, mouse
  • Heat-Shock Proteins
  • NF-kappa B
  • Neoplasm Proteins
  • Receptors, Antigen, T-Cell
  • Sequestosome-1 Protein
  • Sqstm1 protein, mouse
  • Ubiquitin-Conjugating Enzymes
  • Caspases
  • Malt1 protein, mouse
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
  • Atg3 protein, mouse