The Assembly of EDC4 and Dcp1a into Processing Bodies Is Critical for the Translational Regulation of IL-6

Abstract

Macrophages play critical roles in the onset of various diseases and in maintaining homeostasis. There are several functional subsets, of which M1 and M2 macrophages are of particular interest because they are differentially involved in inflammation and its resolution. Here, we investigated the differences in regulatory mechanisms between M1- and M2-polarized macrophages by examining mRNA metabolic machineries such as stress granules (SGs) and processing bodies (P-bodies). Human monocytic leukemia THP-1 cells cultured under M1-polarizing conditions (M1-THPs) had less ability to assemble oxidative-stress-induced SGs than those cultured under M2-polarizing conditions (M2-THPs). In contrast, P-body assembly in response to oxidative stress or TLR4 stimulation was increased in M1-THPs as compared to M2-THPs. These results suggest that mRNA metabolism is controlled differently in M1-THPs and M2-THPs. Interestingly, knocking down EDC4 or Dcp1a, which are components of P-bodies, severely reduced the production of IL-6, but not TNF-α in M1-THPs without decreasing the amount of IL-6 mRNA. This is the first report to demonstrate that the assembly of EDC4 and Dcp1a into P-bodies is critical in the posttranscriptional regulation of IL-6. Thus, improving our understanding of the mechanisms governing mRNA metabolism by examining macrophage subtypes may lead to new therapeutic targets.

Genome-wide QTL mapping results for regional DXA body composition and bone mineral density traits in pigs

“…Consequently, if certain a gene(s) in this region is (are) important for correct calcitonin release or function, an influence on bone mineral traits can be hypothesised. For the QTL affecting BMC and Lean at chr6: 24 770 684-26 159 346 bp, the genes EDC4 and NFATC3 may serve as candidate genes for bone mineral traits for the following reasons: according to Seto et al (2015), the assembly of EDC4 and Dcp1a into processing bodies is critical for the translational regulation of IL-6, which plays a dual role in bone remodelling and bone tumours (Franchimont et al, 2005;Blanchard et al, 2009). Additionally, heterozygous EDC4 knockout mice showed a change in bone density, though it was not significant (Origins of bone and cartilage disease project, 2015).…”

“…However, since similar values for estimation of T scores based on BMD are missing for pigs, this hypothesis has not been verified yet. Based on the fact that the mechanical properties of bones are determined by BMD and bone microarchitecture, another shortcoming of the DXA method is its inability to differentiate between cortical and trabecular bone (Ulrich et al, 1999;Sornay-Rendu et al, 2006). Moreover, it has already been shown that increased body fat causes deviations in BMD measurements by DXA scans and, to a much lesser extent, also in quantitative computed tomography (QCT) (Yu et al, 2012).…”

Tuning innate immunity by translation

“…The amount and composition of SGs and processing bodies (or p-bodies, which are discrete loci of mRNA decay or temporarily sequestering mRNAs away from translation) differ among the subsets of functional macrophages, such as M1 and M2 macrophages [36]. M1 macrophages are involved in acute infection, whereas M2 macrophages engage in tissue remodelling and resolution of inflammation [37].…”

“…M1 macrophages are involved in acute infection, whereas M2 macrophages engage in tissue remodelling and resolution of inflammation [37]. This change is in part attributable to differential expression of p-body assembling proteins Dcp1 and EDC4, which also regulate the amount of synthesized IL6 protein whereas its mRNA remains constant [36]. In addition, M1 macrophages form fewer SGs in response to stress and confer relatively high translation activity under stress [36].…”

“…This change is in part attributable to differential expression of p-body assembling proteins Dcp1 and EDC4, which also regulate the amount of synthesized IL6 protein whereas its mRNA remains constant [36]. In addition, M1 macrophages form fewer SGs in response to stress and confer relatively high translation activity under stress [36]. Hence, differential SG and p-body composition, which differently regulate the translation of inflammatory proteins, impart functional variation in different subsets of macrophages [36].…”