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 certain related peptides on the sodium-coupled transport of D-glucose and of L-leucine was studied by using intestinal brush border membrane vesicles isolated from young rabbits. Kinetic analyses revealed that the NSP4(114-135) peptide, which causes diarrhea in young rodents, is a specific, fully noncompetitive inhibitor of the Na(+)-D-glucose symporter (SGLT1). This interaction involves three peptide-binding sites per carrier unit. In contrast, the Norwalk virus NV(464-483) and mNSP4(131K) peptides, neither of which causes diarrhea, both behave inertly. The NSP4(114-135) and NV(464-483) peptides inhibited Na(+)-L-leucine symport about equally and partially via a different transport mechanism, in that Na(+) behaves as a nonobligatory activator. The selective 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 concomitant inhibition of water reabsorption, is postulated to play a mechanistic role in the pathogenesis of rotavirus diarrhea.
Halaihel
N
N
Institut National de la Santé et de la Recherche Médicale, Unité 510, Faculté de Pharmacie, Université de Paris XI, 92296 Châtenay-Malabry, France.
Liévin
V
V
Ball
J M
JM
Estes
M K
MK
Alvarado
F
F
Vasseur
M
M
D000595:Amino Acid Sequence; D000818:Animals; D012321:DNA-Directed RNA Polymerases; D005947:Glucose / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D007930:Leucine / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D008871:Microvilli / Q000378:metabolism; D008969:Molecular Sequence Data; D009004:Monosaccharide Transport Proteins / Q000037:antagonists & inhibitors*; D010446:Peptide Fragments / Q000633:toxicity*; D011817:Rabbits; D012401:Rotavirus / Q000472:pathogenicity*; D051269:Sodium-Glucose Transporter 1; D017361:Viral Nonstructural Proteins / Q000633:toxicity*
D008562:Membrane Glycoproteins; D009004:Monosaccharide Transport Proteins; D010446:Peptide Fragments; D051269:Sodium-Glucose Transporter 1; D017361:Viral Nonstructural Proteins; D012321:DNA-Directed RNA Polymerases; D007930:Leucine; D005947:Glucose