What is it about?

We demonstrate that proportional flux in the levels of aryl hydrocarbon receptor nuclear translocator (ARNT, the binding partner of AhR) isoforms 1 and 3 modulates AhR signaling in terms of amplitude and expression of distinct gene programs. Molecular studies identified the unique casein kinase 2 (CK2) phosphorylation site within isoform 1 as an essential parameter to the mechanism of ARNT isoform–specific regulation of AhR signaling.

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Why is it important?

Nontoxic agonists and antagonists of the aryl hydrocarbon receptor (AhR) hold high therapeutic potential for treating autoimmune disease and cancer. However, AhR activation by different ligands can lead to opposing phenotypical outcomes in a cell- and tissue- specific manner. In this study, we demonstrate that proportional flux in the levels of aryl hydrocarbon receptor nuclear translocator (ARNT) isoforms 1 and 3 modulates AhR signaling in terms of amplitude and expression of distinct gene programs. These results delineate a molecular mechanism of ARNT isoform–mediated AhR regulation, simplify our understanding of a complex AhR signaling pathway, and provide feasibility for ARNT-targeted therapies that could be used in conjunction with nontoxic AhR ligands for the purpose of therapeutic intervention in hematological diseases via immunomodulation.

Perspectives

This study has developed over years of investigation whereby my group followed the data to what we surmise is an important mechanism for regulating the AhR and, in turn, the activation/differentiation of immune cells. We are quite excited by our findings and how they contribute to our long-term goal of developing new and targeted treatments for hematological diseases, which we acknowledge will take many further studies in order to build upon our current observations. We hope others find these data to be equally exciting and look forward to constructive debate/discussion of our findings and their implications.

Casey Wright
The University of Texas Medical Branch at Galveston

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This page is a summary of: AhR promotes phosphorylation of ARNT isoform 1 in human T cell malignancies as a switch for optimal AhR activity, Proceedings of the National Academy of Sciences, March 2022, Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.2114336119.
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