Degradation Of P47 By Autophagy Contributes To Cadm1 Overexpression In Atll Cells Through The Activation Of Nf-Kappa B

Cell adhesion molecule 1 (CADM1), a member of the immunoglobulin superfamily, is identified as a novel cell surface marker for human T-cell leukemia virus (HTLV-1)-infected T cells. Adult T-cell leukemia/ lymphoma (ATLL) is developed in HTLV-1-infectedT-cells after a long infection period. To examine the mechanism of CADM1 overexpression in ATLL, we first identified that CADM1 is transcriptionally up-regulated by a transcriptional enhancer element through NF-kappa B signaling pathway. In HTLV-1-infected T-cells, CADM1 expression is dependent on HTLV-1/Tax through activation of canonical and non-canonical NF-kappa B; however, in ATLL cells with frequent loss of Tax expression, the activation of canonical NF-kappa B only enhances the CADM1 expression. Along with active mutations in signaling molecules under T-cell recepor (TCR) signaling, degradation of p47, a negative regulator of NF-kappa B, was essential for activation of canonical NF-kappa B through stabilization of NEMO (NF-kappa B essential modulator). The mechanism of p47 degradation is primarily dependent on activation of lysosomal-autophagy and the autophagy is activated in most of the HTLV-infected and ATLL cells, suggesting that the p47 degradation may be a first key molecular event during HTLV-1 infection to T-cells as a connector of two important signaling pathways, NF-kappa B and autophagy.