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HSPG 6-O sulfation (red) is missing from cells with QSulf1 (green).

The interactions of Wnt ligands with their receptors are helped by sulfated extracellular proteins called heparin sulfate proteoglycans (HSPGs). The sulfation state of HSPGs regulates activation of developmental signaling pathways, but it has not been clear how sulfation is controlled. A recently identified candidate, QSulf1, is transiently expressed in myogenic precursors and is required for Wnt-dependent expression of muscle specification genes. On page 341, Ai et al. demonstrate that QSulf1 is a unique sulfatase that remodels the cell surface to turn on Wnt signaling.

QSulf1 has a catalytic domain that resembles a lysosomal 6-O exosulfatase. But Ai and colleagues show that QSulf1 is a 6-O endosulfatase—the first enzyme shown to remove internal sulfates from disaccharides. Cells expressing QSulf1 had extensively different surface HSPGs that were highly desulfated compared with those on neighboring cells.

Desulfation had a positive effect on Wnt signal transduction. Sulfated heparins, in contrast, inhibited Wnt activation of the Frizzled (Fz) receptor. Sulfation appears to affect signaling by regulating the affinity of HSPGs for Wnt. The desulfated version of an HSPG called Glypican1 bound less tightly to Wnt than did fully sulfated Glypican1. The authors suggest that sulfated Glypican1 tends to capture and hold Wnt. Desulfation allows it to pass Wnt to Fz and thus activate Wnt target gene transcription.

Sulfated HSPGs are known to promote, rather than inhibit, FGF signaling. The group expects that HSPGs that interact with FGF should also be substrates for QSulf1, and thus QSulf1 may in this context have a negative regulatory function.

Although QSulf1 normally transits with HSPGs through the Golgi to the cell surface, Golgi-tethered QSulf1 was able to desulfate HSPGs and activate Wnt signaling. If QSulf1 is acting only at the Golgi, sulfation is probably not dynamically regulated. But if QSulf1 also works on the cell surface, it should be easier to modulate its activity and thus regulate Wnt signaling for therapeutic purposes. ▪