Glycan sulfation patterns define autophagy flux at axon tip via PTPRσ-cortactin axis

Chondroitin sulfate (CS) and heparan sulfate (HS) are glycosaminoglycans that both bind the receptor-type protein tyrosine phosphatase PTPRσ, affecting axonal regeneration. CS inhibits axonal growth, while HS promotes it. Here, we have prepared a library of HS octasaccharides and, together with synthetic CS oligomers, we found that PTPRσ preferentially interacts with CS-E—a rare sulfation pattern in natural CS—and most HS oligomers bearing sulfate and sulfamate groups. Consequently, short and long stretches of natural CS and HS, respectively, bind to PTPRσ. CS activates PTPRσ, which dephosphorylates cortactin—herein identified as a new PTPRσ substrate—and disrupts autophagy flux at the autophagosome–lysosome fusion step. Such disruption is required and sufficient for dystrophic endball formation and inhibition of axonal regeneration. Therefore, sulfation patterns determine the length of the glycosaminoglycan segment that bind to PTPRσ and define the fate of axonal regeneration through a mechanism involving PTPRσ, cortactin and autophagy. Sulfation of chondroitin sulfate and heparan sulfate dictates their abilities to promote axon growth via regulating the binding to the phosphatase PTPRσ and the consequences on phosphorylation of the cortactin component of the autophagy machinery.