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

Abstract

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 various 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) activity that can be blocked by the binding of immunosuppressants such as FK506 (7,8). Despite the sequence similarity between the N terminus of ARA9 and the FKBP domains of other immunophilins, ARA9 does not appear to possess isomerase activity or affinity for FK506 (1). We postulate that the structural similarity of ARA9 to the immunophilin family is a reflection of a shared capacity to act as a cellular chaperone, and play a role in the folding and localization of client proteins.The ARA9 protein has been extensively studied in association with the AHR. As a chaperone, ARA9 maintains the AHR in a cytosolic localization, decreases AHR degradation, and increases its ligand binding capacity (9 -11). Although little is known regarding the functional role of ARA9 in PPAR␣ and HBVx function, initial data are consistent with ARA9 acting as a chaperone for these proteins as well (4, 5). We hypothesize that in addition to xenobiotic signaling, the ARA9 protein is also a common chaperone to many proteins involved in a variety of essential cellular functions. This idea is supported by results from whole mount in ...

Aryl Hydrocarbon Receptor Interacting Protein Targets IRF7 to Suppress Antiviral Signaling and the Induction of Type I Interferon

“…Gene targeting studies in mice have revealed that AIP plays essential roles in cardiac development and maintaining productive erythropoiesis (50). In humans, germ line mutations in AIP have been identified and linked to the development of pituitary adenomas (71).…”

“…Infection-Genetic ablation of AIP in mice leads to embryonic lethality caused by cardiac malformation (41,50). To provide genetic evidence for a role of AIP in the regulation of antiviral signaling, we used Aip Ϫ/Ϫ MEFs.…”

Mice with Inactivation of Aryl Hydrocarbon Receptor-Interacting Protein (Aip) Display Complete Penetrance of Pituitary Adenomas with Aberrant ARNT Expression

“…In addition, most mice with reduced Aip expression showed failure of liver vein inclusion resulting in reduced liver size. 17,18 However, possible tumor predisposition was not approached in either study.Here we report a novel conventional Aip knockout mouse, which models the tumor susceptibility caused by human AIP germline mutations. We show that Aip ϩ/Ϫ mice are extremely prone to pituitary tumors, in particular GH secreting adenomas.…”

Phosphodiesterases link the aryl hydrocarbon receptor complex to cyclic nucleotide signaling

“…XAP2 interacts with hepatitis B virus protein X [41], EBNA-3 (Epstein-Barr-virus encoded nuclear antigen 3) [53] and thyroid hormone receptor [54] besides other molecules, like survivin, an anti-apoptotic molecule that has been implicated not only in preservation of cell viability but also in essential regulatory circuitries of cell division [55]. These versatile roles of XAP2 are reflected in the observation that deletion of the XAP2 gene in mice causes embryonic lethality associated with gross defects in the development of the cardiovascular system [56].…”