The Aryl Hydrocarbon Receptor as a Modulator of Anti-viral Immunity

Abstract

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor, which interacts with a wide range of organic molecules of endogenous and exogenous origin, including environmental pollutants, tryptophan metabolites, and microbial metabolites. The activation of AHR by these agonists drives its translocation into the nucleus where it controls the expression of a large number of target genes that include the AHR repressor (AHRR), detoxifying monooxygenases (CYP1A1 and CYP1B1), and cytokines. Recent advances reveal that AHR signaling modulates aspects of the intrinsic, innate and adaptive immune response to diverse microorganisms. This review will focus on the increasing evidence supporting a role for AHR as a modulator of the host response to viral infection.

Keywords: DNA viruses; RNA viruses; aryl hydrocarbon receptor; host response; viral infections.

Figure 1

(A) In stationary state, the aryl hydrocarbon receptor (AHR) is part of a complex composed by the 90kDa heat shock protein (HSP90), the co-chaperone p23 (p23) and the hepatitis B virus X-associated protein (XAP2/AIP/ARA9). The complex stabilizes AHR conformation, protects AHR from proteolitic degradation and contributes to its subcellular localization. The ligand (L) binding triggers a conformational change in AHR exposing a nuclear localization signal (NLS). Then, XAP2 is released from the complex and the L-AHR-HSP90-p23 structure translocates into the nucleus via β-importins. Inside the nucleus, the chaperones are released from the complex and return to the cytoplasm whilst the AHR-L structure heterodimerizes with the aryl hydrocarbon receptor nuclear translocator (ARNT), interacts with its DNA- response-elements -xenobiotics response element (XRE)- and regulates the expression of different genes. The AHR canonical signaling pathway is characterized by the expression of CYP1A1, CYP1B1, CYP2A1, TIPARP and AHRR. Following the modulation of its target genes, the ARNT-AHR-L complex exits the nucleus and is targeted for proteasomal degradation. (B) The AHR non-canonical signaling pathway involves the regulation of cytoplasmic proteins as well as the control of gene expression. Within the cytoplasm, the AHR-L complex can function as an E3 ubiquitin ligase, promoting the proteasomal degradation of target proteins. It also increases the intracellular Ca2+ levels and interacts with different proteins such as PKA, NFκB and Src1. Once in the nucleus, AHR-L is capable of interacting and controlling the activity of other transcription factors (Tf) through transactivation/transrepression or it can exert a Co-activator/Co-Inhibitor role when it is associated with ARNT.

Figure 2

Selected AHR endogenous agonists.

Figure 3

Selected AHR exogenous agonists and antagonists.

Figure 4

Potential roles of AHR during viral infections.