Cholera toxin: a paradigm of a multifunctional protein

Abstract

Cholera toxin (CT) was discovered exactly half a century ago by S.N. De. We have come a long way since this epoch-making discovery. Retrospectively, science had to wait a long time since Koch's prediction of the existence of a toxin, and its actual discovery by De. CT is not just another enterotoxin that causes the signs and symptoms of the dreaded disease, cholera. It is unique in many respects, starting from its structure to its functions. CT is a multifunctional protein that is capable of influencing the immune system in many ways. It not only has remarkable adjuvant properties, but also acts as an anti-inflammatory agent, by modulating specific signal transduction pathways. Its immunomodulatory properties can be harnessed for treatment of various autoimmune disorders, and have shown great promise in the area of immunotherapeutics. CT can truly be considered as a paradigm of a multifunctional protein.

Fig. 1

ADP-ribosylation. The 22kD A1 domain of CT (CTA1) catalyzes the transfer of the ADP-ribose moiety of NAD⁺ to an Arginine residue (Arg²⁰¹) of the α subunit of Gs, leading to defective regulation of adenylyl cyclase and overproduction cAMP.

Fig. 2

Molecular basis of immunomodulation by CTB. MKP1 expression plays a central role in immunomodulation by immunomodulatory agents like CTB. Extracellular inflammatory insult activates MAPK, p38 and JNK pathways, leading to generation of proinflammatory cytokines, resulting in an inflammatory response. Proinflammatory cytokines have an inhibitory effect on MKP1, which leads to further activation of the inflammatory response pathway (left side of diagram). CTB, as well as other anti-inflammatory agents augment MKP1 expression, which leads to inhibition of the pro-inflammatory cascade, thereby attenuating the inflammatory response (right side of diagram). MAPK: mitogen-activated protein kinase; MKP1: MAPK phosphatase-1; JNK: JUN N-terminal kinase.