The virtues and vices of protein citrullination

The post-translational modification of proteins expands the regulatory scope of the proteome far beyond what is achievable through genome regulation. The field of protein citrullination has seen significant progress in the last two decades. The small family of peptidylarginine deiminase (PADI or PAD) enzymes, which catalyse citrullination, have been implicated in virtually all facets of molecular and cell biology, from gene transcription and epigenetics to cell signalling and metabolism. We have learned about their association with a remarkable array of disease states and we are beginning to understand how they mediate normal physiological functions. However, while the biochemistry of PADI activation has been worked out in exquisite detail in vitro, we still lack a clear mechanistic understanding of the processes that regulate PADIs within cells, under physiological and pathophysiological conditions. This review summarizes and discusses the current knowledge, highlights some of the unanswered questions of immediate importance and gives a perspective on the outlook of the citrullination field.