PP2Cδ Controls the Differentiation and Function of Dendritic Cells Through Regulating the NSD2/mTORC2/ACLY Pathway

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.

A histone methylation-MAPK signaling axis drives durable epithelial-mesenchymal transition in hypoxic pancreas cancer

“…However, other transcription factors cooperate with HIF in a tissue-and gene-specific manner (81), which may explain why HIF does not regulate NSD2 transcription in all settings (80). Our work demonstrates that hypoxia can also regulate NSD2 through downregulation of PP2Cδ, which dephosphorylates and destabilizes NSD2 (56), and through MAPK activity. The latter effect may occur through the presence of NSD2 PEST domains, protein motifs that can slow protein turnover when phosphorylated (82,83).…”

“…Changes in NSD2 abundance in hypoxia were insensitive, however, to knockdown of HIF-1α and HIF-2α or inhibition of MEK and JNK (Supp Figure S13C,D) . Searching for possible post-translational mechanisms to explain the elevated expression of NSD2 in hypoxia, we noted that dephosphorylation by PP2Cδ promotes NSD2 proteasomal degradation (56) and recalled that PPM1D , which encodes PP2Cδ, was depleted in hypoxia ( Figure 4I ) . Consistent with the potential mechanism implied, NSD2 expression was elevated in response to PP2Cδ inhibition, and to a lesser degree in response to PP2A inhibition ( Figure 7F ) .…”

Gut microbial GABAergic signaling improves stress-associated innate immunity to respiratory viral infection

“…Oxygen consumption rates (OCR) of MH-S cells were analyzed with an XF-96 Extracellular Flux Analyzer (Seahorse Bioscience) as described [31] . Intracellular ATP concentrations were measured with an ATP Bioluminescence Assay Kit (Beyotime).…”