LDLR, LRP1, and Megalin redundantly participate in the uptake of Clostridium novyi alpha-toxin

Clostridium novyi alpha-toxin (Tcn alpha) also uses LRP1 and Megalin as cellular entry receptors besides LDLR, and this might be a response to cell-type dependent receptor availability for the exotoxin. Clostridium novyi alpha-toxin (Tcn alpha) is a potent exotoxin that induces severe symptoms including gas gangrene, myositis, necrotic hepatitis, and sepsis. Tcn alpha binds to sulfated glycosaminoglycans (sGAG) for cell-surface attachment and utilizes low-density lipoprotein receptor (LDLR) for rapid entry. However, it was also shown that Tcn alpha may use alternative entry receptors other than LDLR. Here, we define that LRP1 and Megalin can also facilitate the cellular entry of Tcn alpha by employing reconstitutive LDLR family proteins. LDLR, LRP1, and Megalin recognize Tcn alpha via their ligand-binding domains (also known as LDL receptor type A repeats). Notably, LDLR and LRP1 have contrasting expression levels in many different cells, thus the dominant entry receptor for Tcn alpha could be cell-type dependent. These findings together increase our knowledge of the Tcn alpha actions and further help to understand the pathogenesis of C. novyi infection-associated diseases.

Automated summary

In addition to LDLR, Clostridium novyi alpha-toxin (Tcn alpha) can also use LRP1 and Megalin as cellular entry receptors. The expression levels of LDLR and LRP1 vary in different cells, suggesting that the dominant entry receptor for Tcn alpha may be cell-type dependent.