Expression of the Phosphatase Ppef2 Controls Survival and Function of CD8+ Dendritic Cells

Abstract

Apoptotic cell death of Dendritic cells (DCs) is critical for immune homeostasis. Although intrinsic mechanisms controlling DC death have not been fully characterized up to now, experimentally enforced inhibition of DC-death causes various autoimmune diseases in model systems. We have generated mice deficient for Protein Phosphatase with EF-Hands 2 (Ppef2), which is selectively expressed in CD8 + DCs, but not in other related DC subtypes such as tissue CD103 + DCs. Ppef2 is down-regulated rapidly upon maturation of DCs by toll-like receptor stimuli, but not upon triggering of CD40. Ppef2-deficient CD8 + DCs accumulate the pro-apoptotic Bcl-2-like protein 11 (Bim) and show increased apoptosis and reduced competitve repopulation capacities. Furthermore, Ppef2 −/− CD8 + DCs have strongly diminished antigen presentation capacities in vivo , as CD8 + T cells primed by Ppef2 −/− CD8 + DCs undergo reduced expansion. In conclusion, our data suggests that Ppef2 is crucial to support survival of immature CD8 + DCs, while Ppef2 down-regulation during DC-maturation limits T cell responses.

PPEF2 Opposes PINK1-Mediated Mitochondrial Quality Control by Dephosphorylating Ubiquitin

“…PPEF2 was independently identified as a survivalassociated phosphatase in another siRNA screening approach interrogating caspase-induced apoptosis (MacKeigan et al, 2005). Similarly, a Ppef2 KO mouse was recently shown to exhibit increased apoptosis in CD8 + dendritic cells (Zwick et al, 2019). This putative role for PPEF2 as an anti-apoptotic phosphatase could also be linked to its interaction with p-S65 ubiquitin and DNA repair (Figure 6), given that uncorrected DNA damage can strongly induce apoptosis (Norbury and Zhivotovsky, 2004).…”

The role of phosphoprotein phosphatases catalytic subunit genes in pancreatic cancer

“…Kutuzov et al identified PPEF2as a suppressor for apoptosis signal regulating kinase-1 (ASK1), a MAP kinase implicated in a variety of diseases, including cancer [ 47 ]. In addition, recent studies revealed that PPEF2 was crucial to support the survival of immature CD8 + dendritic cells, and its down-regulation limited T-cell responses [ 48 ]. PPEF1 and PPEF2 showed low expression in both pancreatic adenocarcinoma and normal tissues in this work.…”