• Register
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.


Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.


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