PTPRS mediates invasion of tetanus neurotoxin into the central nervous system

Tetanus neurotoxin (TeNT) invades the central nervous system (CNS) via retrograde transport through motoneurons. Whether a host factor is needed to mediate TeNT trafficking has remained unknown. Here, using pull-down and mass spectrometry analysis, and by developing a luciferase-based in vivo transport assay, we identify receptor protein tyrosine phosphatase sigma (PTPRS; PTPσ) as the retrograde transport receptor for TeNT. Global or motoneuron-specific PTPRS knockout (KO) abolishes TeNT entry into the CNS in mouse models. PTPRS-TeNT interactions occur in endosomes, prevent toxin translocation, and direct TeNT trafficking in neurons. Structural studies establish that the TeNT light chain and belt region bind to the immunoglobulin domain of PTPRS. Disrupting TeNT-PTPRS interactions blocks TeNT trafficking into the spinal cord; consistently, a PTPRS-binding-deficient TeNT mutant induces botulism-like flaccid paralysis. Thus, PTPRS is the host factor mediating TeNT trafficking into the CNS, revealing a targetable pathway for post-entry intervention and drug delivery into the CNS.