Integrins α1β1 and α2β1 are receptors for the rotavirus enterotoxin

Neung Seon Seo, Carl Q.Y. Zeng, Joseph M. Hyser, Budi Utama, Sue E. Crawford, Kate J. Kim, Magnus Hook, Mary K. Estes

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

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 α1β1 and α2β1 are receptors for NSP4. NSP4 specifically binds to the α1 and α2 I domains with apparent Kd = 1-2.7 μM. 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, E120A, fails to bind α2 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 α2. 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-α2 cells, mouse myoblast cells stably expressing the human α2 integrin. NSP4 colocalizes with integrin α2 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 α2 are attenuated in diarrhea induction in neonatal mice. These results indicate that NSP4 interaction with integrin α1 and α2 is an important component of enterotoxin function and rotavirus pathogenesis, further distinguishing this viral virulence factor from other microbial enterotoxins.

Original languageEnglish (US)
Pages (from-to)8811-8818
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number26
DOIs
StatePublished - Jul 1 2008

Keywords

  • Diarrhea
  • Domain
  • NSP4
  • Signaling

ASJC Scopus subject areas

  • Genetics
  • General

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