Abstract
DEK is a mammalian protein that has been implicated in the pathogenesis of autoimmune diseases and cancer, including acute myeloid leukemia, melanoma, glioblastoma, hepatocellular carcinoma, and bladder cancer. In addition, DEK appears to participate in multiple cellular processes, including transcriptional repression, mRNA processing, and chromatin remodeling. Sub-nuclear distribution of this protein, with the attendant functional ramifications, has remained a controversial topic. Here we report that DEK undergoes acetylation in vivo at lysine residues within the first 70 N-terminal amino acids. Acetylation of DEK decreases its affinity for DNA elements within the promoter, which is consistent with the involvement of DEK in transcriptional repression. Furthermore, deacetylase inhibition results in accumulation of DEK within interchromatin granule clusters (IGCs), sub-nuclear structures that contain RNA processing factors. Overexpression of P/CAF acetylase drives DEK into IGCs, and addition of a newly developed, synthetic, cell-permeable P/CAF inhibitor blocks this movement. To our knowledge, this is the first reported example of acetylation playing a direct role in relocation of a protein to IGCs, and this may explain how DEK can function in multiple pathways that take place in distinct sub-nuclear compartments. These findings also suggest that DEK-associated malignancies and autoimmune diseases might be amenable to treatment with agents that alter acetylation.
Highlights
DEK is a mammalian protein that has been implicated in the pathogenesis of autoimmune diseases and cancer, including acute myeloid leukemia, melanoma, glioblastoma, hepatocellular carcinoma, and bladder cancer
DEK expression is increased in multiple malignancies, including bladder cancer, hepatocellular carcinoma, glioblastoma, melanoma, T-cell large granular lymphocyte leukemia, and acute myeloid leukemia, independent of the t(6,9) chromosomal translocation [1, 2, 7,8,9]
DEK does not belong to any characterized protein family, and sequence similarity with other factors is limited to the SAF box [11, 12], known as the SAP domain [13], a 34-amino acid motif found in nuclear factors that participates in chromatin organization, mRNA processing, and transcription
Summary
We find that acetylation markedly alters the localization of DEK: inhibition of deacetylase activity triggers redistribution of DEK from a diffusely nuclear to a punctate pattern within the nuclear space We show that this pattern results from the accumulation of DEK in structures known as nuclear speckles or interchromatin granule clusters (IGCs), which are well characterized sub-nuclear domains containing RNA-processing and transcription factors. There have been several examples of posttranslational modifications controlling the movement of proteins within the cell, this is the first reported example of acetylation playing a direct role in the relocation of a protein to the IGC It seems that the degree of acetylation, and its regulation, allow DEK to function in multiple pathways that take place in distinct sub-nuclear compartments
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