Deletion of the Aryl Hydrocarbon Receptor-associated Protein 9 Leads to Cardiac Malformation and Embryonic Lethality

Bernice C. Lin, Ruth Sullivan, Youngsook Lee, Susan Moran, Edward Glover, Christopher A. Bradfield
2007 Journal of Biological Chemistry  
The aryl hydrocarbon receptor-associated protein 9, ARA9 (also known as XAP2 or AIP1), is a chaperone that is found in complexes with certain xenobiotic receptors, such as the aryl hydrocarbon receptor (AHR) and the peroxisome proliferatoractivated receptor ␣ (PPAR␣). In an effort to better understand the physiological role of ARA9 outside of its role in xenobiotic signal transduction, we generated a null allele at the Ara9 locus in mice. Mice with a homozygous deletion of this gene die at
more » ... us time points throughout embryonic development. Embryonic lethality is accompanied by decreased blood flow to head and limbs, as well as a range of heart deformations, including double outlet right ventricle, ventricular-septal defects, and pericardial edema. The early cardiovascular defects observed in Ara9-null mice suggest an essential role for the ARA9 protein in cardiac development. The observation that the developmental aberrations in Ara9-null mice are distinct from those observed for disrupted alleles at Ahr or Ppar␣ indicates that the role of ARA9 in cardiac development is independent of its interactions with its known xenobiotic receptor partners. The aryl hydrocarbon receptor-associated protein 9 (ARA9, 2 also known as AIP1) is found in association with two mammalian client proteins, the aryl hydrocarbon receptor (AHR) and the peroxisome proliferator-activated receptor ␣ (PPAR␣) (1-4). The ARA9 protein has also been characterized in association with the hepatitis-B virus X-protein, HBVx. As the result of its interaction with this viral protein, it is also known by the name hepatitis B virus X-associated protein or XAP2 (5). The ARA9 protein is structurally related to the immunophilin family of proteins, harboring an N-terminal FK506 binding (FKBP) domain and C-terminal tetratricopeptide repeats (TPRs) (1, 3, 6) . The FKBP domains of many immunophilin proteins possess peptidyl-prolyl cis-trans isomerase (PPIase) . 2 The abbreviations used are: ARA9, aryl hydrocarbon receptor-associated protein 9; XAP2, hepatits B virus X-associated protein 2; AIP1, aryl hydrocarbon receptor-interacting protein 1; AHR, aryl hydrocarbon receptor; PPAR␣, peroxisome proliferator-activated receptor ␣; FKBP, FK506-binding protein; TPR, tetratricopeptide repeat; PPIase, peptidyl-prolyl isomerase; DORV, double outlet right ventricle; VSD, ventricular septal defect.
doi:10.1074/jbc.m705471200 pmid:17916558 fatcat:zejwa7plg5bi5mfwk5wrxnqm7y