Guo, Tao, Lopez, Dianne M, Wang, Siyuan, Yao, Liudi, Li, Xi, Davies, Elizabeth R., Vargas-Caballero, Mariana, Divecha, Nullin, Schofield, Christopher, Deinhardt, Katrin and Wang, Yihua (2025) Cellular and functional insights into FIH-mediated hydroxylation of TRPA1. The Journal of Biological Chemistry, [110882]. (doi:10.1016/j.jbc.2025.110882).
Abstract
Transient receptor potential cation channel, subfamily A, member 1 (TRPA1), also known as transient receptor potential ankyrin 1, is an ion channel located on the plasma membrane of cells. It is best known as a sensor for pain, cold, and itch in humans and other mammals, as well as for detecting electrophilic sensory irritants, including allyl isothiocyanate (AITC). A previous study confirmed that TRPA1 undergoes hydroxylation at Asn336 by the 2-oxoglutarate oxygenase Factor Inhibiting Hypoxia Inducible Factor (FIH). However, the biological significance of this modification remains unclear. Here, we present cellular and functional studies on the consequences of FIH-mediated asparaginyl hydroxylation of TRPA1. Co-immunoprecipitation experiments indicate that TRPA1 interacts with FIH in cells, in a manner likely involving the FIH dimer interface, as demonstrated by studies with the L340R FIH variant, which is unable to dimerize. Functional studies further suggest that FIH-mediated hydroxylation may be linked to AITC-induced channel activation. This response is diminished or delayed in TRPA1-expressing HEK 293T cells and absent in primary hippocampal cultures when FIH activity is lacking. These findings highlight a potential new avenue for the therapeutic manipulation of TRPA1.
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