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Researchers at University of Tsukuba have proposed a "three-tiered proteostasis model" for describing immune regulation by protein arginine methyltransferases (PRMTs), comprising protein arginine methylation, free methylarginine generation from protein turnover, and methyltransferase-independent interactions with RNA and proteins. The framework integrates emerging evidence linking PRMTs to immune regulation, metabolism, vascular function, and age-associated inflammation.

Tsukuba, Japan—Immune function is regulated not only through gene activation and repression but also through various chemical modifications of intracellular proteins. One such modification is arginine methylation, in which methyl groups are added to arginine residues within proteins. In this review, the researchers synthesize recent evidence showing how PRMT family enzymes regulate gene expression, RNA metabolism, immune signaling, tumor immunity, and age-related chronic inflammation. Further, they discuss potential therapeutic strategies for immune-related diseases.

The researchers also highlight the regulatory roles of PRMTs via mechanisms independent of their methylation activity. To integrate these distinct roles of PRMTs, the researchers propose a three-tiered framework comprising methylation of histone and non-histone proteins (Layer 1), generation of free methylarginines through the turnover of methylated proteins (Layer 2), and methyltransferase-independent functions in which PRMTs modulate cellular processes through RNA and protein interactions (Layer 3). This model provides insights into the link between intracellular protein regulation and broader physiological processes, including immune responses, metabolism, and vascular homeostasis.

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This work was supported by the Japan Society for the Promotion of Science　Grant-in-Aid for Scientific Research (A) (23H00321 and 26H02313 to A.F.) and a grant from AMED-CREST, AMED (JP26gm1410010 to A.F., J.-D. K., and S.T.-F).

Original Paper

Title of original paper:

Arginine methylation in immunoregulation: Mechanisms and therapeutic targeting

Journal:

Cell Chemical Biology

DOI:

10.1016/j.chembiol.2026.09.003

Correspondence

Specially Appointed Professor FUKAMIZU Akiyoshi
Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba

Related Link

Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA)