CCDC22 deficiency in humans blunts activation of proinflammatory NF-kappa B signaling

Starokadomskyy, Petro, Gluck, Nathan, Li, Haiying, Chen, Baozhi, Wallis, Mathew, Maine, Gabriel N., Mao, Xicheng, Zaidi, Iram W., Hein, Marco Y., McDonald, Fiona J., Lenzner, Steffen, Zecha, Agnes, Ropers, Hans-Hilger, Kuss, Andreas W., McGaughran, Julie, Gecz, Jozef and Burstein, Ezra (2013) CCDC22 deficiency in humans blunts activation of proinflammatory NF-kappa B signaling. Journal of Clinical Investigation, 123 5: 2244-2256. doi:10.1172/JCI66466

Author Starokadomskyy, Petro
Gluck, Nathan
Li, Haiying
Chen, Baozhi
Wallis, Mathew
Maine, Gabriel N.
Mao, Xicheng
Zaidi, Iram W.
Hein, Marco Y.
McDonald, Fiona J.
Lenzner, Steffen
Zecha, Agnes
Ropers, Hans-Hilger
Kuss, Andreas W.
McGaughran, Julie
Gecz, Jozef
Burstein, Ezra
Title CCDC22 deficiency in humans blunts activation of proinflammatory NF-kappa B signaling
Formatted title
CCDC22 deficiency in humans blunts activation of proinflammatory NF-κB signaling
Journal name Journal of Clinical Investigation   Check publisher's open access policy
ISSN 0021-9738
Publication date 2013-05-01
Sub-type Article (original research)
DOI 10.1172/JCI66466
Open Access Status DOI
Volume 123
Issue 5
Start page 2244
End page 2256
Total pages 13
Place of publication Ann Arbor, MI United States
Publisher American Society for Clinical Investigation
Collection year 2014
Language eng
Formatted 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.
Keyword Epithelial sodium-channel
Ectodermal dysplasia
Ubiquitin ligase
Transcription factor
Protein interactions
BAC transgeneomics
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Medicine Publications
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