Abstract
Citrullination is the conversion of arginine-to-citrulline by protein arginine deiminases (PADs), whose dysregulation is implicated in the pathogenesis of various types of cancers and autoimmune diseases. Consistent with the ability of human cytomegalovirus (HCMV) to induce post-translational modifications of cellular proteins to gain a survival advantage, we show that HCMV infection of primary human fibroblasts triggers PAD-mediated citrullination of several host proteins, and that this activity promotes viral fitness. Citrullinome analysis reveals significant changes in deimination levels of both cellular and viral proteins, with interferon (IFN)-inducible protein IFIT1 being among the most heavily deiminated one. As genetic depletion of IFIT1 strongly enhances HCMV growth, and in vitro IFIT1 citrullination impairs its ability to bind to 5’-ppp-RNA, we propose that viral-induced IFIT1 citrullination is a mechanism of HCMV evasion from host antiviral resistance. Overall, our findings point to a crucial role of citrullination in subverting cellular responses to viral infection.
Highlights
Citrullination is the conversion of arginine-to-citrulline by protein arginine deiminases (PADs), whose dysregulation is implicated in the pathogenesis of various types of cancers and autoimmune diseases
RT-quantitative real-time PCR (qPCR) analysis revealed that PADI2, 4, and 6 genes were all expressed at significantly higher levels in human cytomegalovirus (HCMV)-infected human foreskin fibroblasts (HFFs) at 24 hpi compared to mock-infected controls (i.e., ~4.8, ~2.7, and ~1.7-fold, respectively) (Fig. 1b)
In contrast to their mRNA expression levels, PAD2 and 4 protein levels were already increased at 24 hpi and remained elevated for up to 72 hpi (Fig. 1d), suggesting that transcription and translation of PADs are differently regulated upon HCMV infection
Summary
Citrullination is the conversion of arginine-to-citrulline by protein arginine deiminases (PADs), whose dysregulation is implicated in the pathogenesis of various types of cancers and autoimmune diseases. A post-translational modification (PTM) that is increasingly recognized to play an essential role in immune-related diseases is citrullination, called deimination, a process where the guanidinium group of arginine is hydrolyzed to form citrulline, a non-genetically encoded amino acid[10]. This PTM is catalyzed by the calcium-dependent protein arginine deiminase (PAD) family of enzymes, which in humans is composed of five isoforms (PADs 1–4 and 6), with different tissue-specific expression and substrate specificities[11]. We unveil a signature of HCMV infection based on PAD-mediated citrullination of multiple cellular proteins to disrupt host -defense mechanisms
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