Abstract
Dendritic cells (DCs) are recognized as a key orchestrator of immune response and homeostasis, deregulation of which may lead to autoimmunity such as experimental autoimmune encephalomyelitis (EAE). Herein we show that the phosphatase PP2Cδ played a pivotal role in regulating DC activation and function, as PP2Cδ ablation caused aberrant maturation, activation, and Th1/Th17-priming of DCs, and hence induced onset of exacerbated EAE. Mechanistically, PP2Cδ restrained the expression of the essential subunit of mTORC2, Rictor, primarily through de-phosphorylating and proteasomal degradation of the methyltransferase NSD2 via CRL4DCAF2 E3 ligase. Loss of PP2Cδ in DCs accordingly sustained activation of the Rictor/mTORC2 pathway and boosted glycolytic and mitochondrial metabolism. Consequently, ATP-citrate lyse (ACLY) was increasingly activated and catalyzed acetyl-CoA for expression of the genes compatible with hyperactivated DCs under PP2Cδ deletion. Collectively, our findings demonstrate that PP2Cδ has an essential role in controlling DCs activation and function, which is critical for prevention of autoimmunity.
Highlights
Dendritic cells (DCs) have been recognized as the most potent antigen-presenting cells with the potential to initiate and orchestrate immune responses [1]
Anti-AKT antibody (4691S), antibody to AKT phosphorylated at Ser473 (4060S), antibody to AKT phosphorylated at Thr308 (13038), anti-mammalian target of rapamycin (mTOR) antibody (2983S), antibody to mTOR phosphorylated at Ser2448 (5536S), anti-phosphatase 2C delta (PP2Cd) antibody (11901S), anti-FoxO1 antibody (2880), anti-Rictor antibody (9476S), anti-Raptor antibody (2280S), anti-H3K36me2 antibody (2901S), anti-H3K27me3 antibody (9733S), antibody to ATP-citrate lyse (ACLY) phosphorylated at Ser455 (4331S), anti-Phosphop70S6Kinase (97596S), anti-p70S6 Kinase (9202s), anti-Phospho-4E-BP1 (2855), anti-4E-BP1 (9644S), anti-H3K9/ 14Ac antibody (9677S), anti-H3K27Ac antibody (8173S) were from Cell Signaling technology; anti-NSD2 antibody, anti-Phospho-serine, anti-ACLY were from Abcam; anti-CUL4B antibody (20882-1-AP) was from Proteintech; anti-NDRG1 antibody and antibody to NDRG1 phosphorylated at Thr346 were from Absin
Flow cytometry analysis of splenocytes revealed that the frequencies of conventional DCs and plasmacytoid DCs were mildly affected by PP2Cd loss, but their numbers were substantially decreased (Figures S1A, B)
Summary
Dendritic cells (DCs) have been recognized as the most potent antigen-presenting cells with the potential to initiate and orchestrate immune responses [1]. The maturation and activation status of DCs has a PP2Cd Controls Dendritic Cells Homeostasis key role in determining immunological activation or tolerance, deregulation of which may result in immunological disorders such as autoimmune diseases [3, 4]. The development and activation of DCs is a coordinated process with the integration of extracellular signals and intracellular pathways. It is a metabolically adaptive process requiring bioenergetics and biosynthesis for cell expansion and effector function. Emerging evidences have shown that immune cells, including DCs, act through mTOR pathway to sense antigenic or metabolic signals and couple them with the environmental cues to instruct cell differentiation. Compared with the well-appreciated role of mTORC1 in immune regulation, our current understanding of mTORC2 is relatively rudimentary
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