The biology of Death Receptor 6: Regulation of CD4+ T cell differentiation and DR6 protein trafficking by the cytoplasmic domain

Members of the tumor necrosis factor receptor superfamily have the ability to cause cell proliferation, differentiation, survival, or apoptosis. Death Receptor 6 (DR6) is expressed broadly in the body, but has clear roles in regulating T cell differentiation and B cell responses. We show here that the DR6 molecule is retained inside cells and is targeted to lysosomes, where it is degraded. Lysosomal targeting was abolished by the deletion of the cytoplasmic domain of DR6 and fine mapping identified an acidic region that contains a DDxxxIL motif as being essential for targeting. Cell surface expression of DR6 was reduced in the presence of TACE and increased in the presence of chloroquine. These results highlight an important regulatory mechanism of DR6 function through trafficking directed by its cytoplasmic domain.