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

Marjorie Hubeau; Flora Ngadjeua; Anne Puel; Laura Israel; Jacqueline Feinberg; Maya Chrabieh; Kiran Belani; Christine Bodemer; Isabelle Fabre; Alessandro Plebani; Stéphanie Boisson-Dupuis; Capucine Picard; Alain Fischer; Alain Israel; Laurent Abel; Michel Veron; Jean-Laurent Casanova; Fabrice Agou; Jacinta Bustamante

doi:10.1182/blood-2010-10-315234

Journal articles

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

Marjorie Hubeau ¹ Flora Ngadjeua ² Anne Puel ¹ Laura Israel ¹ Jacqueline Feinberg ¹ Maya Chrabieh ¹ Kiran Belani ³ Christine Bodemer ⁴ Isabelle Fabre ⁵ Alessandro Plebani ⁶ Stéphanie Boisson-Dupuis ^{1, 7} Capucine Picard ^{1, 8} Alain Fischer ^{8, 9} Alain Israel ¹⁰ Laurent Abel ^{1, 7} Michel Veron ² Jean-Laurent Casanova ^{1, 7, 8} Fabrice Agou ^{2, *} Jacinta Bustamante ^{1, *}

* Corresponding author

1 Inserm U980 - Génétique Humaine des Maladies Infectieuses

2 Biochimie Structurale et Cellulaire

3 Children’s Minnesota Hospital [Minneapolis]

4 Service de dermatologie [CHU Necker]

5 CHU Pointe-à-Pitre/Abymes [Guadeloupe]

6 Università degli Studi di Brescia [Brescia]

7 Rockefeller University [New York]

8 CHU Necker - Enfants Malades [AP-HP]

9 Developpement Normal et Pathologique du Système Immunitaire

10 SMAC - Signalisation Moléculaire et Activation Cellulaire

Abstract : 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.

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Journal articles

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Life Sciences [q-bio]

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

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

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