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Journal Article

CCDC22 deficiency in humans blunts activation of proinflammatory NF-kappaB signaling

MPS-Authors

Lenzner,  S.
Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons50501

Ropers,  H. H.
Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons50401

Kuss,  A. W.
Familial Cognitive Disorders (Luciana Musante), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Starokadomskyy.pdf
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Citation

Starokadomskyy, P., Gluck, N., Li, H., Chen, B., Wallis, M., Maine, G. N., et al. (2013). CCDC22 deficiency in humans blunts activation of proinflammatory NF-kappaB signaling. The Journal of Clinical Investigation, 123(5), 2244-2256. doi:10.1172/JCI66466.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0018-EA7A-6
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.