Citrullination of matrisomal proteins in health and diseases

Abstract

Proteins once translated are subjected to post-translational modifications (PTMs) that can critically modify their characteristics. Citrullination is a unique type of PTM that is catalysed by peptidylarginine deiminase (PAD) enzymes, which regulate a multitude of physiological functions such as apoptosis, gene expression and immune response by altering the structure and function of cellular proteins. However, emerging data have unravelled compelling evidence to support that PAD-mediated citrullination is not exclusive to cellular proteins; rather citrullination of extracellular matrix (ECM) proteins also plays a major contributing role in various physiological/pathological conditions. Here, we discuss putative mechanisms for citrullination-induced alterations in the function of ECM proteins. Further, we put emphasis on influential roles of ECM citrullination in various pathological scenarios to underscore the clinical potential of its manipulation in human diseases. This article is part of the Theo Murphy meeting issue ‘The virtues and vices of protein citrullination’.

Citrullination: new tricks for an old mod

“…The two studies mentioned above, which suggest a role for PADI4 in heart development and demonstrate a non-cell-autonomous role in heart fibrosis, both report that loss of PADI4 leads to the reduction of genes associated with the ECM (Singh et al [ 7 ] ; Van Bruggen et al [ 11 ]). Additionally, an excellent review by Saifi & Ho, details the current knowledge on the mechanisms and functions associated with citrullination of matrisomal proteins [ 12 ]. The authors focus in particular on how aberrant citrullination of such proteins may impact disease development and the clinical potential of manipulating ECM protein citrullination.…”