title: Enhanced sensitivity to cholera toxin in ADP-ribosylarginine hydrolase-deficient mice.
abstract: Cholera toxin (CT) produced by Vibrio cholerae causes the devastating diarrhea of cholera by catalyzing the ADP-ribosylation of the alpha subunit of the intestinal Gs protein (Gsalpha), leading to characteristic water and electrolyte losses. Mammalian cells contain ADP-ribosyltransferases similar to CT and an ADP-ribosyl(arginine)protein hydrolase (ADPRH), which cleaves the ADP-ribose-(arginine)protein bond, regenerating native protein and completing an ADP-ribosylation cycle. We hypothesized that ADPRH might counteract intoxication by reversing the ADP-ribosylation of Gsalpha. Effects of intoxication on murine ADPRH-/- cells were greater than those on wild-type cells and were significantly reduced by overexpression of wild-type ADPRH in ADPRH-/- cells, as evidenced by both ADP-ribose-arginine content and Gsalpha modification. Similarly, intestinal loops in the ADPRH-/- mouse were more sensitive than their wild-type counterparts to toxin effects on fluid accumulation, Gsalpha modification, and ADP-ribosylarginine content. Thus, CT-catalyzed ADP-ribosylation of cell proteins can be counteracted by ADPRH, which could function as a modifier gene in disease. Further, our study demonstrates that enzymatic cross talk exists between bacterial toxin ADP-ribosyltransferases and host ADP-ribosylation cycles. In disease, toxin-catalyzed ADP-ribosylation overwhelms this potential host defense system, resulting in persistence of ADP-ribosylation and intoxication of the cell.
authors.affiliation: Pulmonary-Critical Care Medicine Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Building 10, Room 6D05, MSC 1590, Bethesda, MD 20892-1590, USA.
authors.forename: Jiro
authors.initials: J
authors.lastname: Kato
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Zhu
authors.forename: Chengyu
authors.initials: C
authors.lastname: Liu
authors.forename: Joel
authors.initials: J
authors.lastname: Moss
mesh_terms: D000246:Adenosine Diphosphate Ribose / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D001826:Body Fluids / Q000187:drug effects / Q000378:metabolism; D002384:Catalysis / Q000187:drug effects; D002772:Cholera Toxin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000494:pharmacology; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects; D005091:Exons / Q000235:genetics; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism; D018390:Gene Targeting; D006579:Heterozygote; D007422:Intestines / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050505:Mutant Proteins / Q000378:metabolism; D009699:N-Glycosyl Hydrolases / Q000172:deficiency*; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D050505:Mutant Proteins; D011994:Recombinant Proteins; D000246:Adenosine Diphosphate Ribose; D002772:Cholera Toxin; C043357:ADP-ribosylarginine; D000242:Cyclic AMP; D009699:N-Glycosyl Hydrolases; C046422:ADP-ribosylarginine hydrolase; D019205:GTP-Binding Protein alpha Subunits, Gs