CCDC22 deficiency in humans blunts activation of proinfammatory NF-κB signaling

Petro Starokadomskyy, Nathan Gluck, Haiying Li, Baozhi Chen, Mathew Wallis, Gabriel N. Maine, Xicheng Mao, Iram W. Zaidi, Marco Y. Hein, Fiona J. McDonald, Steffen Lenzner, Agnes Zecha, Hans Hilger Ropers, Andreas W. Kuss, Julie McGaughran, Jozef Gecz, Ezra Burstein

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

NF-κB 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 IκB proteins. In addition, the inactivation of DNA-bound NF-κB 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-κB blockade. Indeed, patient-derived cells demonstrated impaired NF-κB activation due to decreased IκB ubiquitination and degradation. In addition, we found that COMMD8 acted in conjunction with CCDC22 to direct the degradation of IκB proteins. Taken together, our results indicate that CCDC22 participates in NF-κB activation and that its deficiency leads to decreased IκB turnover in humans, highlighting an important regulatory component of this pathway.

Original languageEnglish (US)
Pages (from-to)2244-2256
Number of pages13
JournalJournal of Clinical Investigation
Volume123
Issue number5
DOIs
StatePublished - May 1 2013

ASJC Scopus subject areas

  • Medicine(all)

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    Starokadomskyy, P., Gluck, N., Li, H., Chen, B., Wallis, M., Maine, G. N., Mao, X., Zaidi, I. W., Hein, M. Y., McDonald, F. J., Lenzner, S., Zecha, A., Ropers, H. H., Kuss, A. W., McGaughran, J., Gecz, J., & Burstein, E. (2013). CCDC22 deficiency in humans blunts activation of proinfammatory NF-κB signaling. Journal of Clinical Investigation, 123(5), 2244-2256. https://doi.org/10.1172/JCI66466