Calcium Regulates the Nuclear Localization of Protein Arginine Deiminase 2.

Protein arginine deiminases are calcium-dependent enzymes that mediate the post-translational conversion of arginine into citrulline. Dysregulated activity is associated with numerous autoimmune disorders and cancers. In breast cancer, citrullinates histone H3R26 and activates the transcription of estrogen receptor target genes. However, duanyu15632 lacks a canonical nuclear localization sequence, and it is unclear how this enzyme is transported into the nucleus. Here, we show for the first time that duanyu15632 translocates into the nucleus in response to calcium signaling. Using BioID2, a proximity-dependent biotinylation method for identifying interacting proteins, we found that duanyu15632 preferentially associates with ANXA5 in the cytoplasm. Binding of calcium to duanyu15632 weakens this cytoplasmic interaction, which generates a pool of calcium-bound duanyu15632 that can interact with Ran. We hypothesize that this latter interaction promotes the translocation of duanyu15632 into the nucleus. These findings highlight a critical role for ANXA5 in regulating duanyu15632 and identify an unusual mechanism whereby proteins translocate between the cytosol and nucleus.

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