"Enzyme Behind Immune Cell Response Revealed"

[ivorin]

Arginine methylation catalyzed by PRMT1 is required for B cell activation and differentiation

Study: https://www.nature.com/articles/s41467-017-01009-1

Article:
https://scienmag.com/enzyme-behind-immune-cell-response-revealed/

Arginine methylation catalyzed by protein arginine methyltransferases (PRMT) is a common post-translational modification in mammalian cells, regulating many important functions including cell signalling, proliferation and differentiation. Here we show the role of PRMT1 in B-cell activation and differentiation. PRMT1 expression and activity in human and mouse peripheral B cells increases in response to in vitro or in vivo activation. Deletion of the Prmt1 gene in mature B cells establishes that although the frequency and phenotype of peripheral B cell subsets seem unaffected, immune responses to T-cell-dependent and -independent antigens are substantially reduced. In vitro activation of Prmt1-deficient B cells with a variety of mitogens results in diminished proliferation, differentiation and survival, effects that are correlated with altered signal transduction from the B cell receptor. Thus PRMT1 activity in B cells is required for correct execution of multiple processes that in turn are necessary for humoral immunity.

 

[aimossy]

From the Introduction:

Methylation of arginine is the most abundant type of protein methylation in mammalian cells and is a major modulator of protein function1. The three identified types of modified arginine are monomethylated arginine (MMA), asymmetric dimethylated arginine (ADMA) and symmetric dimethylated arginine (SDMA), all catalyzed by one of the nine known protein arginine methyltransferases (PRMT)1,2,3. ADMA formation is catalyzed by type I PRMTs (comprising PRMT1, 2, 3, 4, 6 and 8), SDMA by type II (PRMT5) and MMA by type III (PRMT7)1. The importance of the modifications catalyzed by these enzymes is indicated by embryonic lethality of PRMT1-deficient and PRMT5-deficient mice4, 5 and by the severe phenotype of PRMT2, PRMT3, PRMT4 and PRMT6-deficient mice6,7,8,9.

PRMT1 is the major arginine methyltransferase active in mammalian cells and is required for normal embryogenesis, cell cycle progression, cell viability, and signal transduction1, 2, 6, 10. PRMT1 methylates histones, RNA-binding proteins (RBPs), cell cycle proteins and proteins involved in regulating gene transcription, including high-mobility group proteins (HMGA) and runt-related transcription factor 1 (RUNX1)1, 2. PRMT1 is also an active component of signal transduction pathways including those from the B-cell receptor (BCR), T-cell receptor (TCR), nerve growth factor receptor, type 1 interferon receptor, and the pathway involving NF-AT11,12,13,14,15,16. PRMT1 is also known to directly regulate the activity of forkhead box protein O1 (FOXO1)17 and Bcl-2-associated death promoter (BAD)18, proteins associated with cell viability. In these examples, the motif RxRxxS/T recognized by protein kinase B (PKB) and present in both FOXO1 and BAD, overlaps with sites recognized by PRMT1, leading to competition in which methylation by PRMT1 inhibits phosphorylation by PKB, thereby prolonging the localization of FOXO1 in the nucleus in one case and inhibiting the pro-apoptotic activity of BAD in the other17, 18. Clearly, arginine methylation catalyzed by PRMT1 is crucial to a multitude of pathways although the regulation of its activity is unclear in the majority of cases.

From the discussion section:

Asymmetrically dimethylated arginine proteins are present in naive B cells before increasing in amount significantly following B-cell activation. Given that we found protein methylation activity to be essentially undetectable in naive B cells over a 3-h interval in vitro, this result implies that arginine methylation is a particularly stable post-translational change in these cells. Interestingly, we observed several novel asymmetrically methylated protein bands in both control and Prmt1-deficient B-cell samples following stimulation, indicating unique and redundant substrates of PRMT1 that presumably participate in the processes that are dysregulated in the enzyme’s absence. Identifying these substrates and the activities that are dependent on PRMT1 will be the basis of significant future work, determining how methylation modulates their roles in proliferation, differentiation and survival following B-cell activation by a variety of stimuli.

Mady Hornig has stated previously (not published) that asymmetric dimethylarginine was notably low in their cohort findings.

short duration ME/CFS patients (those in the first few years of illness) are showing significantly reduced levels of ADMA (asymmetric dimethylarginine). This could be quite significant, because this would cause oxidative stress – and as she noted earlier, that could be a key factor in promoting autoimmunity