An emerging literature is implicating the ST6Gal-l sialyltransferase in regulating some aspect of cell differentiation status, as well as cell survival. Work from our group has shown that ST6Gal-l is downregulated during monocyte differentiation along the macrophage lineage [1,2], and similar studies from other groups have shown that ST6Gal-l is downregulated during T cell activation [3,4] and dendritic cell maturation [5,6], ST6Gal-l is overexpressed in myeloid leukemia cells [7], and interestingly, it has recently been reported that induced pluripotent stem cells (iPSCs) have increased expression of ST6Gal-1 relative to the differentiated somatic cell population that was used to create iPSCs [8], Based on these collective findings, we hypothesize that ST6Gal-l activity promotes a proliferative vs. differentiated phenotype, and that the loss of ST6Gal-l during immune cell differentiation/maturation sensitizes cells to apoptotic stimuli thus limiting immune cell lifespan. However, despite the extensive correlative evidence linking ST6Gal-l expression to a pro-survival cell phenotype, there is virtually nothing known regarding mechanism. Our work has advanced our understanding of the importance of ST6Gal-l by showing that ST6Gal-l sialylates two specific death receptors. Fas and TNFR1, and that this sialylation event in turn blocks apoptotic signaling from these receptors. Taken together, these results highlight a new paradigm for apoptotic signaling, and further reveal new insights into mechanisms that regulate immune cell survival.
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