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

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46 Citations (Scopus)

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

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Ubiquitination
Proteins
Intellectual Disability
Ectodermal Dysplasia
Immune System Diseases
Proteolysis
Copper
Inflammation
Mutation
DNA
Genes
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

Cite this

CCDC22 deficiency in humans blunts activation of proinfammatory NF-κB 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; Burstein, Ezra.

In: Journal of Clinical Investigation, Vol. 123, No. 5, 01.05.2013, p. 2244-2256.

Research output: Contribution to journalArticle

Starokadomskyy, P, Gluck, N, Li, H, Chen, B, Wallis, M, Maine, GN, Mao, X, Zaidi, IW, Hein, MY, McDonald, FJ, Lenzner, S, Zecha, A, Ropers, HH, Kuss, AW, McGaughran, J, Gecz, J & Burstein, E 2013, 'CCDC22 deficiency in humans blunts activation of proinfammatory NF-κB signaling', Journal of Clinical Investigation, vol. 123, no. 5, pp. 2244-2256. https://doi.org/10.1172/JCI66466
Starokadomskyy P, Gluck N, Li H, Chen B, Wallis M, Maine GN et al. CCDC22 deficiency in humans blunts activation of proinfammatory NF-κB signaling. Journal of Clinical Investigation. 2013 May 1;123(5):2244-2256. https://doi.org/10.1172/JCI66466
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. / CCDC22 deficiency in humans blunts activation of proinfammatory NF-κB signaling. In: Journal of Clinical Investigation. 2013 ; Vol. 123, No. 5. pp. 2244-2256.
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AU - Wallis, Mathew

AU - Maine, Gabriel N.

AU - Mao, Xicheng

AU - Zaidi, Iram W.

AU - Hein, Marco Y.

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AU - Lenzner, Steffen

AU - Zecha, Agnes

AU - Ropers, Hans Hilger

AU - Kuss, Andreas W.

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AU - Gecz, Jozef

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