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Paper Reading 01 Etomoxir Actions on Regulatory and Memory T Cells Are Independent of Cpt1a-Mediated  BrendaRaud, Luciana Berod, et al. Fatty acid oxidation is generally considered an important energy resource for Treg cells and memory T cells to supports their survival. However, this paper pointed that inhibition of FAO has no influence on the generation of memory T cells or the differentiation of Treg cells. Cpt1a is the rate-limiting enzyme for LC-FAO, which catalyzes the esterification of long-chain acyls with carnitine to form acylcarnitine, allows fatty acid moiety to be transported into mitochondrial matrix to finally generates ATP. The authors generated mice with a specific deletion of Cpt1a in T cells, even the palmitate utilization was impaired, T cell homeostasis in TCpt1a mice was not affected, which suggested ACC2/Cpt1a axis is not required for T cell homeostasis or primary immune responses in vivo. They further demonstrated in vitro that Cpt1ais dispensable for both the generation of Tmem cells and the differentiation of Treg cells. Furthermore, Etomoxir, an inhibitor of Cpt1a did not affect Treg cell differentiation at 3 μM but only high doses of etomoxir(>100 μM) reduced Foxp3 expression in iTreg cultures, they found there is off-targets effect of 100 μM etomoxir through inhibit adenine nucleotide translocator (ANT), then reduce the abundance of citrate and other TCA cycle intermediates. These results revealed that FAO is dispensable for the generation and activation of Treg cells and memory T cells, and etomoxir inhibit Treg cells independent on the Cpt1 inhibition and FAO but through inhibit ANTto affect mitochondrial respiration. https:///10.1016/j.cmet.2018.06.002 02 Jixiao Niu, Yang Sun, Xu Wu, et al.? Nature volume?573,?pages139–143(2019) STAT3 is an important regulator of immunity, inflammation and tumorigenesis, the mainly activation forms of STAT3 are tyrosine phosphorylation and dimerization induced by cytokine and growth factor. Whether other factors could affect the activity of STAT3 is poorly known. In this study, the author identified that STAT3 is palmitoylated at the SRC homology 2 (SH2) domain by using chemical reporters of protein palmitoylation, and palmitoyl (C16) and stearoyl (C18) are the major acyl groups for STAT3 modification. The palmitoylation of STAT3 at C687S/C712S sites enhanced its nuclear localization, and IL-6 could significantly promote the palmitoylation level. The authors further identified that ZDHHC19 is the palmitoyl acyltransferase mediated STAT3 palmitoylation, when they generated the catalytically inactive ZDHHC19(C142S) mutant by mutating active-site cysteine residue to serine18, STAT3 was failed to be palmitoylated under basal conditions or with IL-6 stimulation. In addition, knockdown of ZDHHC19 using short hairpin (sh)RNA blocked STAT3 palmitoylation and expression of its target genes, and ZDHHC19 knockout significantly blocked the tumor growth induced by an HFD diet in a xenograft model of HCC95 cells in mice. These results indicate the S-palmitoylation of STAT3 is critical for its homodimerization, nuclear localization and transcriptional activity, and provide a novel insight on the biological functions of fatty acids in cells especially immunes cells. END |
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