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New mechanism of X-linked anhidrotic ectodermal dysplasia with immunodeficiency: impairment of ubiquitin binding despite normal folding of NEMO protein.

Nuclear factor-κB essential modulator (NEMO), the regulatory subunit of the IκB kinase complex, is a critical component of the NF-κB pathway. Hypomorphic mutations in the X-linked human NEMO gene cause various forms of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID). All known X-linked EDA-ID-causing mutations impair NEMO protein expression, folding, or both. We describe here 2 EDA-ID-causing missense mutations that affect the same residue in the CC2-LZ domain (D311N and D311G) that do not impair NEMO production or folding. Structural studies based on pull-down experiments showed a defect in noncovalent interaction with K63-linked and linear polyubiquitin chains for these mutant proteins. Functional studies on the patients' cells showed an impairment of the classic NF-κB signaling pathways after activation of 2 NEMO ubiquitin-binding-dependent receptors, the TNF and IL-1β receptors, and in the CD40-dependent NF-κB pathway. We report the first human NEMO mutations responsible for X-linked EDA-ID found to affect the polyubiquitin binding of NEMO rather than its expression and folding. These experiments demonstrate that the binding of human NEMO to polyubiquitin is essential for NF-κB activation. They also demonstrate that the normal expression and folding of NEMO do not exclude a pathogenic role for NEMO mutations in patients with EDA-ID.

Pubmed ID: 21622647


  • Hubeau M
  • Ngadjeua F
  • Puel A
  • Israel L
  • Feinberg J
  • Chrabieh M
  • Belani K
  • Bodemer C
  • Fabre I
  • Plebani A
  • Boisson-Dupuis S
  • Picard C
  • Fischer A
  • Israel A
  • Abel L
  • Veron M
  • Casanova JL
  • Agou F
  • Bustamante J



Publication Data

July 28, 2011

Associated Grants

  • Agency: NCRR NIH HHS, Id: 5UL1RR024143-03

Mesh Terms

  • Blotting, Western
  • Ectodermal Dysplasia 1, Anhidrotic
  • Enzyme Activation
  • Female
  • Humans
  • I-kappa B Kinase
  • Immunologic Deficiency Syndromes
  • Male
  • Mutation, Missense
  • NF-kappa B
  • Pedigree
  • Protein Binding
  • Protein Folding
  • Signal Transduction
  • Ubiquitin
  • Young Adult