Functional Divergence in the Role of N-Linked Glycosylation in Smoothened Signaling

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N-linked glycosylation is a post-translational modification occurring on membrane proteins such as G protein-coupled receptors (GPCR). Smoothened (Smo) is a GPCR that functions as the signal transducer of the Hedgehog (Hh) pathway. We used a mutagenesis approach to assess the role of N-glycans in Smo signaling in two genetic models for Hh pathway activity, Drosophila and mouse. In doing so, we discovered a divergence in glycan function between them. We mapped an essential N-glycan acceptor site that when lost in Drosophila, triggered ER retention, altered Smo protein stability and blunted its signaling capacity. Conversely, ER exit of the murine protein was unaffected by glycan loss, as was its ability to traffic and induce a G protein-independent signal to activate Hh target genes. However, the ability of vertebrate Smo to induce a distinct G protein-dependent signal was lost. This suggests that N-linked glycosylation may influence signal bias of vertebrate Smo to favor one signal output over the other. We therefore propose that the role of this conserved post-translational modification may have been repurposed from governing Smo ER exit in the fly to influencing effector route selection in vertebrates.

Vyšlo v časopise: Functional Divergence in the Role of N-Linked Glycosylation in Smoothened Signaling. PLoS Genet 11(8): e32767. doi:10.1371/journal.pgen.1005473
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005473

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