Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 26, Pages 8811-8818Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0803934105
Keywords
domain; diarrhea; signaling; NSP4
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Funding
- NIAID NIH HHS [R01 AI020624, T32 AI007471, AI20624, R01 AI080656, T32AI007471, R56 AI020624] Funding Source: Medline
- NIDDK NIH HHS [P30 DK056338, DK30144, R01 DK030144, R56 DK030144, DK56338] Funding Source: Medline
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Rotavirus NSP4 is a viral enterotoxin capable of causing diarrhea in neonatal mice. This process is initiated by the binding of extracellular NSP4 to target molecule(s) on the cell surface that triggers a signaling cascade leading to diarrhea. We now report that the integrins alpha 1 beta 1 and alpha 2 beta 1 are receptors for NSP4. NSP4 specifically binds to the alpha 1 and alpha 2 I domains with apparent K-d = 1-2.7 mu M. Binding is mediated by the I domain metal ion-dependent adhesion site motif, requires Mg2+ or Mn2+, is abolished with EDTA, and an NSP4 point mutant, E(120)A, fails to bind alpha 2 integrin I domain. NSP4 has two distinct integrin interaction domains. NSP4 amino acids 114-130 are essential for binding to the I domain, and NSP4 peptide 114-135 blocks binding of the natural ligand, collagen I, to integrin alpha 2. NSP4 amino acids 131-140 are not associated with the initial binding to the I domain, but elicit signaling that leads to the spreading of attached C2C12-alpha 2 cells, mouse myoblast cells stably expressing the human alpha 2 integrin. NSP4 colocalizes with integrin alpha 2 on the basolateral surface of rotavirus-infected polarized intestinal epithelial (Caco-2) cells as well as surrounding noninfected cells. NSP4 mutants that fail to bind or signal through integrin alpha 2 are attenuated in diarrhea induction in neonatal mice. These results indicate that NSP4 interaction with integrin alpha 1 and alpha 2 is an important component of enterotoxin function and rotavirus pathogenesis, further distinguishing this viral virulence factor from other microbial enterotoxins.
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