Calcium Regulates the Nuclear Localization of Protein Arginine Deiminase 2

Protein arginine
deiminases (PADs) are calcium-dependent enzymes
that mediate the post-translational conversion of arginine into citrulline.
Dysregulated PAD activity is associated with numerous autoimmune disorders
and cancers. In breast cancer, PAD2 citrullinates histone H3R26 and
activates the transcription of estrogen receptor target genes. However,
PAD2 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 PAD2 translocates into the nucleus in response
to calcium signaling. Using BioID2, a proximity-dependent biotinylation
method for identifying interacting proteins, we found that PAD2 preferentially
associates with ANXA5 in the cytoplasm. Binding of calcium to PAD2
weakens this cytoplasmic interaction, which generates a pool of calcium-bound
PAD2 that can interact with Ran. We hypothesize that this latter interaction
promotes the translocation of PAD2 into the nucleus. These findings
highlight a critical role for ANXA5 in regulating PAD2 and identify
an unusual mechanism whereby proteins translocate between the cytosol
and nucleus.