A/B toxins such as cholera toxin, Pseudomonas exotoxin and killer toxin K28 contain a KDEL-like amino acid motif at one of their subunits which ensures retrograde toxin transport through the secretory pathway of a target cell. As key step in host cell invasion, each toxin binds to distinct plasma membrane receptors that are utilized for cell entry. Despite intensive efforts, some of these receptors are still unknown. Here we identify the yeast H/KDEL receptor Erd2p as membrane receptor of K28, a viral A/B toxin carrying an HDEL motif at its cell binding β-subunit. While initial toxin binding to the yeast cell wall is unaffected in cells lacking Erd2p, binding to spheroplasts and in vivo toxicity strongly depend on the presence of Erd2p. Consistently, Erd2p is not restricted to membranes of the early secretory pathway but extends to the plasma membrane where it binds and internalizes HDEL-cargo such as K28 toxin, GFP^HDEL and Kar2p. Since human KDEL receptors are fully functional in yeast and restore toxin sensitivity in the absence of endogenous Erd2p, toxin uptake by H/KDEL receptors at the cell surface might likewise contribute to the intoxication efficiency of A/B toxins carrying a KDEL-motif at their cytotoxic A-subunit(s).

Spinal cord injury (SCI) results in the production of proinflammatory cytokines due to inflammasome activation. Lipocalin 2 (LCN2) is a small secretory glycoprotein upregulated by toll-like receptor (TLR) signaling in various cells and tissues. LCN2 secretion is induced by infection, injury, and metabolic disorders. In contrast, LCN2 has been implicated as an anti-inflammatory regulator. However, the role of LCN2 in inflammasome activation during SCI remains unknown. This study examined the role of Lcn2 deficiency in the NLRP3 inflammasome-dependent neuroinflammation in SCI. Lcn2^−/− and wild-type (WT) mice were subjected to SCI, and locomotor function, formation of the inflammasome complex, and neuroinflammation were assessed. Our findings demonstrated that significant activation of the HMGB1/PYCARD/caspase-1 inflammatory axis was accompanied by the overexpression of LCN2 7 days after SCI in WT mice. This signal transduction results in the cleaving of the pyroptosis-inducing protein gasdermin D (GSDMD) and the maturation of the proinflammatory cytokine IL-1β. Furthermore, Lcn2^−/− mice showed considerable downregulation in the HMGB1/NLRP3/PYCARD/caspase-1 axis, IL-1β production, pore formation, and improved locomotor function compared with WT. Our data suggest that LCN2 may play a role as a putative molecule for the induction of inflammasome-related neuroinflammation in SCI.