Cadherin-related family member 3, a childhood asthma susceptibility gene product, mediates rhinovirus C binding and replication

Proc Natl Acad Sci U S A. 2015 Apr 28;112(17):5485-90. doi: 10.1073/pnas.1421178112. Epub 2015 Apr 6.

Abstract

Members of rhinovirus C (RV-C) species are more likely to cause wheezing illnesses and asthma exacerbations compared with other rhinoviruses. The cellular receptor for these viruses was heretofore unknown. We report here that expression of human cadherin-related family member 3 (CDHR3) enables the cells normally unsusceptible to RV-C infection to support both virus binding and replication. A coding single nucleotide polymorphism (rs6967330, C529Y) was previously linked to greater cell-surface expression of CDHR3 protein, and an increased risk of wheezing illnesses and hospitalizations for childhood asthma. Compared with wild-type CDHR3, cells transfected with the CDHR3-Y529 variant had about 10-fold increases in RV-C binding and progeny yields. We developed a transduced HeLa cell line (HeLa-E8) stably expressing CDHR3-Y529 that supports RV-C propagation in vitro. Modeling of CDHR3 structure identified potential binding sites that could impact the virus surface in regions that are highly conserved among all RV-C types. Our findings identify that the asthma susceptibility gene product CDHR3 mediates RV-C entry into host cells, and suggest that rs6967330 mutation could be a risk factor for RV-C wheezing illnesses.

Keywords: CDHR3; receptor; rhinovirus C.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Asthma
  • Cadherins* / chemistry
  • Cadherins* / genetics
  • Cadherins* / metabolism
  • Cells, Cultured
  • Genetic Predisposition to Disease
  • HeLa Cells
  • Humans
  • Membrane Proteins* / chemistry
  • Membrane Proteins* / genetics
  • Membrane Proteins* / metabolism
  • Models, Molecular*
  • Point Mutation*
  • Polymorphism, Single Nucleotide*
  • Protein Structure, Tertiary
  • Rhinovirus / physiology*
  • Risk Factors
  • Virus Internalization
  • Virus Replication / physiology*

Substances

  • CDHR3 protein, human
  • Cadherins
  • Membrane Proteins

Associated data

  • GEO/GSE61396