Citrullination and the protein code: crosstalk between post-translational modifications in cancer

Abstract

Post-translational modifications (PTMs) of proteins are central to epigenetic regulation and cellular signalling, playing an important role in the pathogenesis and progression of numerous diseases. Growing evidence indicates that protein arginine citrullination, catalysed by peptidylarginine deiminases (PADs), is involved in many aspects of molecular and cell biology and is emerging as a potential druggable target in multiple diseases including cancer. However, we are only just beginning to understand the molecular activities of PADs, and their underlying mechanistic details in vivo under both physiological and pathological conditions. Many questions still remain regarding the dynamic cellular functions of citrullination and its interplay with other types of PTMs. This review, therefore, discusses the known functions of PADs with a focus on cancer biology, highlighting the cross-talk between citrullination and other types of PTMs, and how this interplay regulates downstream biological events. This article is part of the Theo Murphy meeting issue ‘The virtues and vices of protein citrullination’.

Orthogonal Translation for Site-Specific Installation of Post-translational Modifications

“…The guanidinium group also losses two hydrogen-bond donors but obtains two hydrogen-bond acceptor sites . Protein citrullination regulates a variety of cellular processes, including gene expression, cell signaling, metabolism, and apoptosis. , It is associated with a variety of human diseases, including cancers, inflammatory and autoimmune disorders, cardiovascular diseases, and neurodegeneration diseases . Citrullination is catalyzed by peptidyl arginine deiminases (PADs) .…”

Citrullination: new tricks for an old mod

“…Consequently, cancer cell lines have traditionally provided useful systems for studying PADI-mediated signaling and transcription. A comprehensive review article by the La Thangue laboratory summarizes the current knowledge of citrullination in cancer and details known mechanisms of cross-talk between citrullination and other PTMs (Koyo et al [ 22 ]). This article provides an excellent primer for future research that will both help understand mechanisms of action of PADIs in pathophysiology and help integrate citrullination into better-understood molecular mechanisms and cellular functions.…”

Pathological functions and therapeutic targets of post-translational modifications in pan-cancer

“…The vast diversity of PTMs, as well as their intricate crosstalk, is intricately connected to numerous pivotal signaling events that underpin neoplastic transformation, carcinogenesis, and metastasis. 2,3 Various PTMs play imperative pathological roles encompassing all facets of cancer hallmark functions, cancer metabolism, and regulation of the tumor microenvironment. Although previous studies have revealed some effects of PTMs on cancer, 2 our understanding of whether a common regulatory pattern exists for such modifications across multiple cancer types, as well as the interplay between different types of PTMs and the intricate regulatory network they collectively form, remains limited.…”