Aberrant calcium signaling by transglutaminase-mediated posttranslational modification of inositol 1,4,5-trisphosphate receptors

Significance Reversible and repetitive structural changes are essential for ligand-gated ion channels to mediate biological signaling. The inositol 1,4,5-trisphosphate receptor (IP ₃R) assembles ligand-gated ion channels that mediate calcium signaling. IP ₃ activates channels at a distance by reversible allosteric changes in the IP ₃R tetramer. Here we show a new mode of posttranslational modification that irreversibly blocks allosteric changes in the IP ₃R. We identified an IP ₃R-modifying enzyme as tissue transglutaminase that inhibits IP ₃R function by locking subunit configurations. This modification chronically impaired calcium signaling and autophagy regulation in living cells, and up-regulated modification was observed in Huntington disease models. To our knowledge, this is the first demonstration of transglutaminase-catalyzed posttranslational modification in ligand-gated channel allostery and provides a new framework for enzymatic regulation of allostery. The inositol 1,4,5-trisphosphate receptor (IP ₃R) in the endoplasmic reticulum mediates calcium signaling that impinges on intracellular processes. IP ₃Rs are allosteric proteins comprising four subunits that form an ion channel activated by binding of IP ₃ at a distance. Defective allostery in IP ₃R is considered crucial to cellular dysfunction, but the specific mechanism remains unknown. Here we demonstrate that a pleiotropic enzyme transglutaminase type 2 targets the allosteric coupling domain of IP ₃R type 1 (IP ₃R1) and negatively regulates IP ₃R1-mediated calcium signaling and autophagy by locking the subunit configurations. The control point of this regulation is the covalent posttranslational modification of the Gln2746 residue that transglutaminase type 2 tethers to the adjacent subunit. Modification of Gln2746 and IP ₃R1 function was observed in Huntington disease models, suggesting a pathological role of this modification in the neurodegenerative disease. Our study reveals that cellular signaling is regulated by a new mode of posttranslational modification that chronically and enzymatically blocks allosteric changes in the ligand-gated channels that relate to disease states.