Abstract
Nucleotide-sugar transporters (NSTs) transport nucleotide-sugar conjugates into the Golgi lumen where they are then used in the synthesis of glycans. We previously reported crystal structures of a mammalian NST, the CMP-sialic acid transporter (CST) (Ahuja and Whorton 2019). These structures elucidated many aspects of substrate recognition, selectivity, and transport; however, one fundamental unaddressed question is how the transport activity of NSTs might be physiologically regulated as a means to produce the vast diversity of observed glycan structures. Here, we describe the discovery that an endogenous methylated form of cytidine monophosphate (m5CMP) binds and inhibits CST. The presence of m5CMP in cells results from the degradation of RNA that has had its cytosine bases post-transcriptionally methylated through epigenetic processes. Therefore, this work not only demonstrates that m5CMP represents a novel physiological regulator of CST, but it also establishes a link between epigenetic control of gene expression and regulation of glycosylation.
Highlights
Glycosylation is the most common form of protein and lipid modification [1,2,3,4]
We show that m5CMP inhibits CMP-sialic acid (CMP-Sia) transport, and a crystal structure of CMP-sialic acid transporter (CST) in complex with m5CMP provides insight into the molecular mechanism of highaffinity interaction between m5CMP and CST
Considering that m5CMP inhibits CMP-Sia transport and that m5CMP cellular concentrations are primarily related to post-transcriptional methylation of RNA, these results suggest a link between RNA epigenetics and regulation of cellular glycosylation
Summary
Glycosylation is the most common form of protein and lipid modification [1,2,3,4]. Glycosylation affects protein folding, stability, and activity, and impacts nearly every aspect of biology. Most glycosylation occurs in the ER and Golgi lumens, where glycosyltransferase enzymes build glycan chains by transferring sugars from nucleotide-coupled sugar donors to glycan acceptors. For these reactions to occur, nucleotide-coupled sugars must be transported from the cytoplasm, where they are synthesized, across the ER and Golgi membranes and into the lumenal space. This is accomplished by a family of proteins called nucleotide sugar transporters (NSTs) [5,6,7]. Many factors are thought to affect the generation of diverse glycosylation patterns, with one being the availability of nucleotide sugars in the Golgi lumen. One of the primary factors that controls the availability of nucleotide sugars in the Golgi lumen is the transport activity of NSTs, yet little is known about what cellular processes may regulate NST activity
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