Background: Mutations in the NEMO ZF cause various forms of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID). Results:The NEMO ZF contains a larger ubiquitin binding surface, which is required for IKK/NF-B activation. Conclusion:This study provides an understanding of how defective mutations of NEMO ZF in NF-B signaling leads to the EDA-ID pathology. Significance: This study provides novel insights in the NEMO ZF-dependent mechanisms for IKK activation in NF-B signaling.