The aryl hydrocarbon receptor-interacting protein in cancer and immunity: Beyond a chaperone protein for the dioxin receptor

Abstract

The aryl hydrocarbon receptor (AhR)-interacting protein (AIP) is a ubiquitously expressed, immunophilin-like protein best known for its role as a co-chaperone in the AhR-AIP-Hsp90 cytoplasmic complex. In addition to regulating AhR and the xenobiotic response, AIP has been linked to various aspects of cancer and immunity that will be the focus of this review article. Loss-of-function AIP mutations are associated with pituitary adenomas, suggesting that AIP acts as a tumor suppressor in the pituitary gland. However, the tumor suppressor mechanisms of AIP remain unclear, and AIP can exert oncogenic functions in other tissues. While global deletion of AIP in mice yields embryonically lethal cardiac malformations, heterozygote, and tissue-specific conditional AIP knockout mice have revealed various physiological roles of AIP. Emerging studies have established the regulatory roles of AIP in both innate and adaptive immunity. AIP interacts with and inhibits the nuclear translocation of the transcription factor IRF7 to inhibit type I interferon production. AIP also interacts with the CARMA1-BCL10-MALT1 complex in T cells to enhance IKK/NF-κB signaling and T cell activation. Taken together, AIP has diverse functions that vary considerably depending on the client protein, the tissue, and the species.

Keywords: aryl hydrocarbon receptor (AhR); aryl hydrocarbon receptor-interacting protein (AIP); cancer; chaperones; immunity; pituitary adenoma.

Figure 1

AhR activation pathway. Inactivated AhR is found in the cytoplasm, bound to AIP and a dimer of Hsp90. Upon ligand binding, AhR undergoes a conformational change and sheds its chaperone proteins. AhR then translocates to the nucleus where it binds to the AhR nuclear translocator (ARNT), and xenobiotic response elements (XREs) in gene promoters to upregulate the expression of AhR target genes.

Figure 2

Schematic of AIP structure. The peptidyl propyl cis-trans isomerase (PPIase) and tetratricopeptide repeat (TPR) domains and the corresponding amino acids are indicated. The areas of AIP that interact with AhR, Hsp90, and IRF7 are indicated in the lines below. The amino acids that are essential for AIP interaction with AhR are highlighted in blue. The amino acid (Thr40) that is phosphorylated by TBK1 and increases AIP interaction with IRF7 is indicated in red.

Figure 3

AIP regulation of innate and adaptive immune signaling pathways.A, in the RIG-I-like receptor (RLR) pathway, RIG-I senses 5′-triphosphate double-stranded RNA genomes from RNA viruses, and activates the mitochondrial adaptor MAVS (mitochondrial anti-viral signaling molecule). Activated MAVS forms large prion-like aggregates that recruit TRAF E3 ubiquitin ligases (TRAF2, 3, 5, 6) leading to TBK1 activation. TBK1 phosphorylates AIP at Thr40, which serves as a molecular switch for AIP binding to IRF7 and preventing its nuclear translocation. The AIP-IRF7 interaction suppresses the expression of type I IFNs and interferon-stimulated genes. B, following T-cell receptor activation, PKCθ is activated and phosphorylates CARMA1. AIP interacts with and stabilizes CARMA1 in its open conformation, thus enhancing the complex formation of CARMA1 with BCL10 and MALT1. The activated CBM complex triggers IKK and NF-κB signaling.

Figure 4

Tumor suppressor function of AIP in somatotrophs.A, AIP regulates RET signaling to promote apoptosis. GDNF (glial cell-derived neurotrophic factor) binding to the RET receptor promotes cell survival through AKT signaling. In wild-type AIP somatotrophs (top), AKT cell survival signaling is balanced by the pro-apoptotic RET/caspase-3/PKCδ pathway. In this pathway, AIP promotes the shuttling of caspase-3 and PKCδ to the intracellular (IC) portion of the RET receptor. Caspase-3 cleaves the IC portion of RET and PKCδ which activates the pro-apoptotic p53 pathway. However, in somatotrophs expressing loss of function AIP or no AIP (bottom), the RET/caspase-3/PKCδ pathway is downregulated and the pro-survival GDNF-mediated RET/AKT pathway predominates over the pro-apoptotic RET/caspase-3/PKCδ pathway thus predisposing to pituitary adenoma formation. B, AIP regulates cAMP signaling through its interaction with the inhibitory Gα_i subunit (top). When AIP is mutated or deleted, cAMP signaling is dysregulated. The increased cAMP promotes PKA-mediated GH production and cellular proliferation.

Figure 5

AIP promotes survivin stability and its mitochondrial import via TOM20. AIP functions as a chaperone to enhance the stability of the anti-apoptotic protein survivin. AIP also interacts with the mitochondrial import receptor TOM20 to facilitate the shuttling of survivin to the mitochondria, where it is imported and exerts its anti-apoptotic functions.