Autophagy Another Selective Path to Destruction

John F. Foley

Science Signaling, AAAS, Washington, DC 20005, USA

One of the consequences of T cell stimulation through the T cell receptor (TCR) is activation of the transcription factor nuclear factor B (NF-B), which is required for the expression of genes the products of which mediate T cell activation and proliferation (see commentary by Blonska and Lin). TCR-stimulated NF-B activation occurs through the assembly of a complex of the proteins CARMA1, MALT1, and Bcl10 (the CBM complex), which recruits the inhibitor of B (IB) kinase (IKK) complex through interactions between the IKK adaptor subunit NEMO and lysine 63 (K63)–linked polyubiquitin chains attached to Bcl10. Paul et al. found that TCR stimulation of a T cell line led to the colocalization of Bcl10 and MALT1 with LC3 and ATG12, components of the autophagy machinery that are required for the formation of autophagosomes and the degradation of cellular components. Furthermore, TCR stimulation of primary mouse effector T cells, but not naïve T cells, resulted in the degradation of Bcl10. TCR stimulation resulted in the K63-linked polyubiquitination of Bcl10 and its association with the autophagy adaptor protein p62. Surprisingly, in addition to inhibiting TCR-dependent degradation of Bcl10, loss of p62 also resulted in defective activation of NF-B. Confocal microscopy analysis of wild-type and mutant Bcl10 proteins showed that polyubiquitination of Bcl10 at lysines 31 and 63 was required for the association of Bcl10 with p62 and autophagosomes. Experiments with autophagy inhibitors showed that the initial TCR-dependent recruitment of Bcl10 and MALT1 to autophagosomes was followed by the autophagic degradation of Bcl10 and the release of MALT1, which was found in aggregates. Inhibition of autophagy led to enhanced TCR dependent–NF-B activation by suppressing the degradation of Bcl10. Together, these data suggest that the selective autophagic degradation of Bcl10 provides a mechanism to inhibit TCR dependent–NF-B activation.

S. Paul, A. K. Kashyap, W. Jia, Y.-W. He, B. C. Schaefer, Selective autophagy of the adaptor protein Bcl10 modulates T cell receptor activation of NF-B. Immunity 36, 947–958 (2012). [PubMed]

M. Blonska, X. Lin, Dampening NF-B signaling by "self-eating". Immunity 36, 895–896 (2012). [PubMed]

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