1. CCDC22 deficiency in humans blunts activation of proinflammatory NF-κB signaling
- Author
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Ezra Burstein, Petro Starokadomskyy, Baozhi Chen, Hans-Hilger Ropers, Andreas W. Kuss, Marco Y. Hein, Haiying Li, Julie McGaughran, Fiona J. McDonald, Agnes Zecha, Xicheng Mao, Jozef Gecz, Nathan Gluck, Mathew Wallis, Iram W. Zaidi, Steffen Lenzner, and Gabriel N. Maine
- Subjects
Genetic Linkage ,NF-KappaB Inhibitor alpha ,Ubiquitin ,Ectodermal Dysplasia ,Neoplasms ,Humans ,Transcription factor ,Adaptor Proteins, Signal Transducing ,Inflammation ,Regulation of gene expression ,Chromosomes, Human, X ,biology ,HEK 293 cells ,NF-kappa B ,Proteins ,Signal transducing adaptor protein ,General Medicine ,NFKB1 ,Molecular biology ,Protein Structure, Tertiary ,Ubiquitin ligase ,Cell biology ,HEK293 Cells ,Gene Expression Regulation ,Microscopy, Fluorescence ,Mutation ,biology.protein ,I-kappa B Proteins ,Signal transduction ,Carrier Proteins ,Research Article ,HeLa Cells ,Signal Transduction - Abstract
NF-kappaB is a master regulator of inflammation and has been implicated in the pathogenesis of immune disorders and cancer. Its regulation involves a variety of steps, including the controlled degradation of inhibitory IkappaB proteins. In addition, the inactivation of DNA-bound NF-kappaB is essential for its regulation. This step requires a factor known as copper metabolism Murr1 domain-containing 1 (COMMD1), the prototype member of a conserved gene family. While COMMD proteins have been linked to the ubiquitination pathway, little else is known about other family members. Here we demonstrate that all COMMD proteins bind to CCDC22, a factor recently implicated in X-linked intellectual disability (XLID). We showed that an XLID-associated CCDC22 mutation decreased CCDC22 protein expression and impaired its binding to COMMD proteins. Moreover, some affected individuals displayed ectodermal dysplasia, a congenital condition that can result from developmental NF-kappaB blockade. Indeed, patient-derived cells demonstrated impaired NF-kappaB activation due to decreased IkappaB ubiquitination and degradation. In addition, we found that COMMD8 acted in conjunction with CCDC22 to direct the degradation of IkappaB proteins. Taken together, our results indicate that CCDC22 participates in NF-kappaB activation and that its deficiency leads to decreased IkappaB turnover in humans, highlighting an important regulatory component of this pathway.
- Published
- 2013
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