Second messenger Ap₄A polymerizes target protein HINT1 to transduce signals in FcεRI-activated mast cells.

ABSTRACT: Signal transduction systems enable organisms to monitor their external environments and accordingly adjust the cellular processes. In mast cells, the second messenger Ap₄A binds to the histidine triad nucleotide-binding protein 1 (HINT1), disrupts its interaction with the microphthalmia-associated transcription factor (MITF), and eventually activates the transcription of genes downstream of MITF in response to immunostimulation. How the HINT1 protein recognizes and is regulated by Ap₄A remain unclear. Here, using eight crystal structures, biochemical experiments, negative stain electron microscopy, and cellular experiments, we report that Ap₄A specifically polymerizes HINT1 in solution and in activated rat basophilic leukemia cells. The polymerization interface overlaps with the area on HINT1 for MITF interaction, suggesting a possible competitive mechanism to release MITF for transcriptional activation. The mechanism depends precisely on the length of the phosphodiester linkage of Ap₄A. These results highlight a direct polymerization signaling mechanism by the second messenger.

SUBMITTER: Yu J 

PROVIDER: S-EPMC6789022 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature