Arginine methylation of hnRNPK negatively modulates apoptosis upon DNA damage through local regulation of phosphorylation

Abstract

Heterogeneous nuclear ribonucleoprotein K (hnRNPK) is an RNA/DNA-binding protein involved in chromatin remodeling, RNA processing and the DNA damage response. In addition, increased hnRNPK expression has been associated with tumor development and progression. A variety of post-translational modifications of hnRNPK have been identified and shown to regulate hnRNPK function, including phosphorylation, ubiquitination, sumoylation and methylation. However, the functional significance of hnRNPK arginine methylation remains unclear. In the present study, we demonstrated that the methylation of two essential arginines, Arg296 and Arg299, on hnRNPK inhibited a nearby Ser302 phosphorylation that was mediated through the pro-apoptotic kinase PKCδ. Notably, the engineered U2OS cells carrying an Arg296/Arg299 methylation-defective hnRNPK mutant exhibited increased apoptosis upon DNA damage. While such elevated apoptosis can be diminished through addition with wild-type hnRNPK, we further demonstrated that this increased apoptosis occurred through both intrinsic and extrinsic pathways and was p53 independent, at least in part. Here, we provide the first evidence that the arginine methylation of hnRNPK negatively regulates cell apoptosis through PKCδ-mediated signaling during DNA damage, which is essential for the anti-apoptotic role of hnRNPK in apoptosis and the evasion of apoptosis in cancer cells.

Induction of DUSP14 ubiquitination by PRMT5‐mediated arginine methylation

“…The methylation of p53 at the Lys372 residue induces acetylation at adjacent lysine residues, resulting in activation of p53 transcriptional activity (30). In addition, protein methylation regulates phosphorylation (31, 32). Arginine methylation of the DNA/RNA-binding protein heterogeneous nuclear ribonucleoprotein K inhibits its phosphorylation by PKCδ, resulting in enhancement of heterogeneous nuclear ribonucleoprotein K–mediated cell apoptosis (31).…”

“…In addition, protein methylation regulates phosphorylation (31, 32). Arginine methylation of the DNA/RNA-binding protein heterogeneous nuclear ribonucleoprotein K inhibits its phosphorylation by PKCδ, resulting in enhancement of heterogeneous nuclear ribonucleoprotein K–mediated cell apoptosis (31). Furthermore, PRMT1-mediated arginine methylation of Axin induces its phosphorylation by glycogen synthase kinase 3 β, leading to decreased ubiquitination and subsequent stabilization of Axin (32).…”

Comparative Monomethylarginine Proteomics Suggests that Protein Arginine Methyltransferase 1 (PRMT1) is a Significant Contributor to Arginine Monomethylation in Toxoplasma gondii

“…Phosphorylation and arginine methylation are often mutually exclusive [e.g. (55)], but arginine methylation can also promote phosphorylation (56). Proteins detected in the phosphoproteome of tachyzoites are enriched in genes that are up-regulated at several time points during cell cycle, including mid-G1 phase (27).…”

Protein arginine methyltransferase 1 (PRMT1) represses MHC II transcription in macrophages by methylating CIITA

“…At this point, it is not clear what arginine residues within CIITA are targeted by PRMT1. In addition, it remains undetermined whether PRMT1-induced CIITA degradation is solely a result of PRMT1-dependent arginine methylation or a secondary effect contingent on communications with other types of post-translational modifications since PRMT1-dependent arginine methylation has been shown to form crosstalk with acetylation2627, ubiquitination2829, and phosphorylation3031. It has been previously shown that CIITA poly-ubiquitination plays a role in regulating its stability20, although CIITA mono-ubiquitination could enhance its activity without altering its half-life32.…”