Cholera toxin internalization and intoxication.

We read, with considerable dismay, a recent Research Article on cholera toxin (CT) internalization (Torgersen et al., 2001), in which the authors extensively challenged methods, results and conclusions that we had published four years ago (Orlandi and Fishman, 1998). As space limits a point-by-point rebuttal of their comments and critique of the many deficiencies in their study, we encourage readers to evaluate our response by comparing both papers. As a preface to our reply, we state that most aspects of CT intoxication are generally accepted, such as its structure and receptor, its mechanism of retrograde trafficking through the Golgi and ER, its mechanism of activating adenylyl cyclase and its pathophysiological effects on human enterocytes. However, we believe that the crux of the dispute is our differing views on the relationship between CT internalization and intoxication. Whereas most of the cellsurface-bound CT is internalized, only a small percentage is activated on release of the enzymatic A1 peptide (Kassis et al., 1982; Orlandi and Fishman, 1998). Thus, to understand the mechanism of CT action, one must determine not only the pathway(s) for CT internalization but also whether the uptake leads to intoxication of the cell.