Novel transcript variants of TRAIL show different activities in activation of NF-κB and apoptosis

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Aims Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has many transcript variants, but whether they possess distinct function is not completely known. In the present study, we compared the function of these TRAIL variants. Main methods A bioinformatics analysis was performed to examine potential TRAIL variants. For the functional study, over-expression of TRAIL isoforms was used to examine their NF-κB inducing and apoptotic activities in both cancer and normal cells. Moreover, soluble TRAIL E4 variant protein was expressed and purified in prokaryotic cells, and was used for apoptotic assay. Key findings We cloned seven truncated TRAIL variants, designated as AK, E2, E3, E4, DA, BX424, and BX439. In comparison with the wild type TRAIL protein expressed from full-length RefSeq, over-expression of all these TRAIL variants activated NF-κB and its targeting genes in human cells at varying degrees. Some isoforms including BX424, DA and E4 even showed NF-κB, IL8, CCL4 and CCL20 promoter activating activity stronger than the wild type protein. All truncated variant proteins had no toxicity to normal human cells, similar to the wild type protein; however, they all failed to induce apoptosis in cancer cells that are sensitive to TRAIL. Recombinant soluble TRAIL E4 protein also failed to antagonize TRAIL-induced apoptosis in cancer cells. Significance Truncated TRAIL variant proteins lost apoptotic activity but retained or even enhanced the NF-κB activating potentials, these results suggest that TRAIL variants may play roles in non-apoptotic cellular processes that are more important than we previously thought.