Human COMMD1 ELISA Matched Antibody Pair

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

The COMM domain containing (COMMD) family of proteins represents a recently discovered set of evolutionarily conserved factors characterized by the presence of a defining carboxy-terminal motif. In vertebrates, there are ten members of the family, and among their emerging functions the control of the transcription factor NFkB has been most extensively studied. NF kappa B plays a critical role in a number of homeostatic processes in multicellular organisms, including the regulation of immunity and cell survival. COMMD proteins inhibit NFkB mediated gene expression, and recent mechanistic studies have revealed that COMMD1 controls the ubiquitination of NF kappa B subunits, an event linked to transcriptional termination. COMMD1 binds to a multimeric ubiquitin ligase containing Elongins B/C, Cul2 and SOCS1 (ECSSOCS1). In this complex, COMMD1 facilitates the binding of NFkB subunits to the ligase, thereby promoting their ubiquitination and degradation. Additional insights gained from these studies indicate that COMMD proteins likely play a broader role in cellular homeostasis through their participation in the ubiquitination pathway.