CC2D1A, a DM14 and C2 domain protein, activates NF-kappaB through the canonical pathway.
CC2D1A is an evolutionarily conserved protein that contains four DM14 domains at the N terminus and a C2 domain at the C terminus. Loss-of-function mutations in CC2D1A have been linked to mental retardation in human, but the biochemical function of this protein is largely unknown. Here, we show that CC2D1A is a potent activator of NF-kappaB. The activation of NF-kappaB by CC2D1A requires its C2 domain. CC2D1A activates NF-kappaB in a manner that depends on the ubiquitin-conjugating enzyme Ubc13, TNF receptor-associated factor TRAF2, the protein kinase TAK1, and the IkappaB kinase (IKK) complex. In addition, the deubiquitination enzyme Cylindromatosis (CYLD) negatively regulates the activity of CC2D1A. These results suggest that CC2D1A activates NF-kappaB through the canonical IKK pathway.
Department of Molecular Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9148, USA.
Meng
M
Zhao
Xiao-Dong
XD
Li
Zhijian
Z
Chen
D002460:Cell Line; D004268:DNA-Binding Proteins / Q000737:chemistry*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000737:chemistry*; D008954:Models, Biological; D016328:NF-kappa B / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000737:chemistry; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000737:chemistry; D000099151:MAP Kinase Kinase Kinase 7
D004268:DNA-Binding Proteins; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D047992:TNF Receptor-Associated Factor 2; D025801:Ubiquitin; D000099151:MAP Kinase Kinase Kinase 7; C512283:CC2D1A protein, human