Abstract
Simple SummaryDysregulated fucosylation has been characterized as an underlying cause or a contributor to the pathogenesis of several disease states. However, to date, there is not a clear understanding of how and what proteins, signaling pathways, and cellular processes are impacted by fucosylation. Here, we characterized the proteins recognized by a fucose-binding lectin and unexpectedly discovered that many intracellular proteins are putatively subject to posttranslational fucosylation. We further found that fucosylation on intracellular ribosomal protein S3 responds to stimulus, and that it appears to be independent of the currently characterized fucosylation pathway. This work suggests a to-date-underappreciated role for fucosylation on intracellular proteins and supports the existence of fucosylation capabilities within cells that is not fully known.Alterations in genes encoding for proteins that control fucosylation are known to play causative roles in several developmental disorders, such as Dowling-Degos disease 2 and congenital disorder of glycosylation type IIc (CDGIIc). Recent studies have provided evidence that changes in fucosylation can contribute to the development and progression of several different types of cancers. It is therefore important to gain a detailed understanding of how fucosylation is altered in disease states so that interventions may be developed for therapeutic purposes. In this report, we find that fucosylation occurs on many intracellular proteins. This is an interesting finding, as the fucosylation machinery is restricted to the secretory pathway and is thought to predominately affect cell-membrane-bound and secreted proteins. We find that Ribosomal protein S3 (RPS3) is fucosylated in normal tissues and in cancer cells, and that the extent of its fucosylation appears to respond to stress, including MAPK inhibitors, suggesting a new role in posttranslational protein function. Our data identify a new ribosome-independent species of fucosylated RPS3 that interacts with proteins involved in posttranscriptional regulation of RNA, such as Heterogeneous nuclear ribonucleoprotein U (HNRNPU), as well as with a predominance of non-coding RNAs. These data highlight a novel role for RPS3, which, given previously reported oncogenic roles for RPS3, might represent functions that are perturbed in pathologies such as cancer. Together, our findings suggest a previously unrecognized role for fucosylation in directly influencing intracellular protein functions.
Highlights
Glycosylation, the posttranslational modification of proteins and lipids with sugars, plays an important role in regulating protein–protein interactions, protein–ligand signaling, and cellular behaviors, during development [1,2,3]
We found that Heterogeneous nuclear ribonucleoprotein U (HNRNPU) does localize to the cytoplasmic fraction by both subcellular fractionation and immunofluorescence analysis, and its steady state protein levels are increased in melanoma cell lines relative to primary cells (Figure S4A,B), consistent with those of
Decreased fucosylation of Ribosomal protein S3 (RPS3) in response to treatment was associated with a decrease in binding to several RNAs we identified by RIP-Chip and a decrease in interaction with HNRNPU (Figure 5C–E)
Summary
Glycosylation, the posttranslational modification of proteins and lipids with sugars, plays an important role in regulating protein–protein interactions, protein–ligand signaling, and cellular behaviors, during development [1,2,3]. Growing evidence has highlighted active roles that alterations in glycosylation in post-developmental disease states (e.g., cancer) can play in disease development and/or progression. Interventions designed to modify or target defects or alterations in glycosylation in disease states have shown promise as therapeutic strategies. Characterizing the substrates that are subject to fucosylation and understanding how fucosylation influences their function, downstream signaling, and cellular behavior, are expected to highlight how and in which context(s) fucosylation might be exploited as a viable therapeutic target or to identify the key proteins and cellular signaling pathways that respond to alterations in fucosylation and may themselves be targeted for therapeutic intervention
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
