Direct inhibitory effect of rotavirus NSP4(114-135) peptide on the Na+-D-glucose symporter of rabbit intestinal brush border membrane

The direct effect of a rotavirus nonstructural glycoprotein, NSP4, and cert ain related peptides on the sodium-coupled transport of D-glucose and of L- leucine was studied by using intestinal brush border membrane vesicles isol ated from young rabbits. Kinetic analyses revealed that the NSP4(114-135) p eptide, which causes diarrhea in young rodents, is a specific, fully noncom petitive inhibitor of the Na+-D-glucose symporter (SGLT1). This interaction involves three peptide-binding sites per carrier unit. In contrast, the No rwalk virus NV(464-483) and mNSP4(131K) peptides, neither of which causes d iarrhea, both behave inertly. The NSP4(114-135) and NV(464-483) peptides in hibited Na+-L-leucine symport about equally and partially via a different t ransport mechanism, in that Na+ behaves as a nonobligatory activator. The s elective and strong inhibition caused by the NSP4(114-135) peptide on SGLT1 in vitro suggests that during rotavirus infection in vivo, NSP4 can be one effector directly causing SGLT1 inhibition. This effect, implying a concom itant inhibition of water reabsorption, is postulated to play a mechanistic role in the pathogenesis of rotavirus diarrhea.