Shiga toxin and epidermal growth factor uptake pathways

Shigellosis, which is characterized by diarrhea and dysentery, is a worldwide human health problem caused by the Shigella group of bacteria (Niyogi, 2005). These bacteria produce a toxin, Shiga toxin, that is comprised of two components referred to as A and B, in which the A subunit is the enzymatically active toxin responsible for inactivation of the 28s ribosomal RNA, and the B subunit is required for binding and entry into target cells after transport across the polarized epithelial cells of the gut from their apical surface (for reviews see Johannes and Goud, 1998, 2000; O’Loughlin and Robins-Browne, 2001; Sandvig and van Deurs, 2002; Spooner et al., 2006). How Shiga toxin is able to enter and intoxicate cells is of great medical interest; therefore, this has been studied extensively (Sandvig et al., 1992; Mallard et al., 1998, 2002). The Shiga toxin B subunit (STxB) binds to Gb3, a neutral glycosphingolipid at the surface of target cells in the gut vasculature, as well as in the kidney and brain and is then internalized by a combination of clathrinmediated and clathrinindependent endocytic pathways (Sandvig et al., 1989; Nichols et al., 2001; for review see O’Loughlin and Robins-Browne, 2001). Once internalized, Shiga toxin is then transported directly from early and recycling endosomes to the trans-Golgi network (Mallard et al., 1998; Bonifacino and Rojas, 2006). This pathway is dependent on the function of clathrin and dynamin ( Lauvrak et al., 2004), the small GTP-binding protein Rab6 and its effector proteins, the lipid phosphatase OCRL1, a defi ned set of SNAREs (Mallard et al., 2002; Monier et al., 2002; Tai et al., 2004; Choudhury et al., 2005; Hyvola et al., 2006), and a second GTP-binding protein Arl1 and its effector golgin-97 (Lu et al., 2004). From the TGN, the toxin is then transported by a retrograde pathway dependent on Rab6 through the Golgi apparatus to the ER (Sandvig et al., 1992; White et al., 1999), where the toxin A subunit enters the cytoplasm most likely by retrotranslocation (for review see Sandvig and van Deurs, 2002). Despite the multistep nature of the Shiga toxin uptake pathway, only a single Rab GTP-binding protein, Rab6, has been shown to play any role in its transport (Girod et al., 1999; White et al., 1999; Mallard et al., 2002). Because each membrane traffi cking step is thought to involve a discrete set of Rabs (Zerial and McBride, 2001), it seems likely that additional Rabs are involved in Shiga toxin uptake. To further defi ne the pathway Specifi c Rab GTPase-activating proteins defi ne the Shiga toxin and epidermal growth factor uptake pathways