The virtues and vices of protein citrullination

Abstract

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.

Keywords: citrullination; disease; peptidylarginine deiminase; protein.

Figure 1.

Organismal functions of citrullination in physiology and disease. (a) Under physiological conditions, PADIs are activated in response to stimuli such as infection, hormone stimulation, developmental signals and, possibly, hypoxia. Depending on their tissue expression, PADIs can regulate skin homeostasis, nerve myelination, immune responses and embryo development. PADI6, which is considered to be catalytically inactive, is not included in this schematic. (b) When one of the activating signals or the level of PADI activity are deregulated, aberrant levels of citrullination can underlie the development of skin disorders, multiple sclerosis, cancer progression, metastasis and autoimmunity. Deregulation of NETosis can exacerbate autoimmunity, cancer metastasis and tissue destruction associated with a number of disease states. Lack of PADI6 leads to compromised female fertility.

Figure 2.

Modes and outcomes of PADI4 activation in the immune system. Schematic representation of the outcomes of PADI4 activation in neutrophils. Upon infection, active PADI4 can citrullinate histones to mediate transcriptional activation of inflammatory cytokines. Increased inflammatory signalling can lead to histone hypercitrullination and NETosis, which can cause tissue destruction and exacerbate a number of pathologies.