Protein arginine methyltransferase 5 promotes cholesterol biosynthesis–mediated Th17 responses and autoimmunity
Lindsay M. Webb, Shouvonik Sengupta, Claudia Edell, Zayda L. Piedra-Quintero, Stephanie A. Amici, Janiret Narvaez Miranda, Makenzie Bevins, Austin Kennemer, Georgios Laliotis, Philip N. Tsichlis, Mireia Guerau-de-Arellano
Lindsay M. Webb, Shouvonik Sengupta, Claudia Edell, Zayda L. Piedra-Quintero, Stephanie A. Amici, Janiret Narvaez Miranda, Makenzie Bevins, Austin Kennemer, Georgios Laliotis, Philip N. Tsichlis, Mireia Guerau-de-Arellano
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Research Article Autoimmunity Immunology

Protein arginine methyltransferase 5 promotes cholesterol biosynthesis–mediated Th17 responses and autoimmunity

Abstract

Protein arginine methyltransferase 5 (PRMT5) catalyzes symmetric dimethylation (SDM) of arginine, a posttranslational modification involved in oncogenesis and embryonic development. However, the role and mechanisms by which PRMT5 modulates Th cell polarization and autoimmune disease have not yet been elucidated. Here, we found that PRMT5 promoted SREBP1 SDM and the induction of cholesterol biosynthetic pathway enzymes that produce retinoid-related orphan receptor (ROR) agonists that activate RORγt. Specific loss of PRMT5 in the CD4+ Th cell compartment suppressed Th17 differentiation and protected mice from developing experimental autoimmune encephalomyelitis (EAE). We also found that PRMT5 controlled thymic and peripheral homeostasis in the CD4+ Th cell life cycle and invariant NK (iNK) T cell development and CD8+ T cell maintenance. This work demonstrates that PRMT5 expression in recently activated T cells is necessary for the cholesterol biosynthesis metabolic gene expression program that generates RORγt agonistic activity and promotes Th17 differentiation and EAE. These results point to Th PRMT5 and its downstream cholesterol biosynthesis pathway as promising therapeutic targets in Th17-mediated diseases.

Authors

Lindsay M. Webb, Shouvonik Sengupta, Claudia Edell, Zayda L. Piedra-Quintero, Stephanie A. Amici, Janiret Narvaez Miranda, Makenzie Bevins, Austin Kennemer, Georgios Laliotis, Philip N. Tsichlis, Mireia Guerau-de-Arellano

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Figure 1

Constitutive and inducible CD4+ Prmt5-KO models.

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Constitutive and inducible CD4+ Prmt5-KO models. (A) Schematic of Prmt5 ...
(A) Schematic of Prmt5 long and short isoform transcripts and Prmt5 genomic locus targeting strategy. Exon 7, an exon common to all protein-coding Prmt5 isoforms, was flanked by loxP sites to provide deletion of both isoforms in Cre-expressing cells. (B) Schematic of expected PRMT5 deletion in thymus T cell precursors and peripheral T cells in 2 different transgenic models, namely T-PRMT5Δ/Δ (constitutive) and iCD4-PRMT5Δ/Δ (inducible). (C and D) PCR amplification of genomic DNA isolated from CD4+ and CD8+ T cells from (C) T-PRMT5Δ/Δ or (D) iCD4-PRMT5Δ/Δ mice, as well as control PRMT5fl/fl mice. PRMT5-KO band: 283 bp; full-length floxed PRMT5 band: 1100 bp. DN, double negative; DP, double positive; SP, single positive.