bims-stacyt Biomed News
on Paracrine crosstalk between cancer and the organism
Issue of 2019‒06‒23
four papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

  1. Cell Stress. 2018 May 08. 2(5): 119-121
    Kim SB, Cho S, Kim S.
      Previous work by Kim, et al. (2017) unveiled that lysyl-tRNA synthetase (KRS) is secreted through a mechanism involving syntenin-containing exosomes. They described how KRS, commonly known as part of the translational machinery in the cytoplasm, is secreted into the extracellular space where it induces inflammation. First, KRS secretion is triggered by starvation conditions. The increase in caspase-8 levels during starvation is responsible for proteolysis and generation of the N-terminal truncated form of KRS, and this event is required for KRS dissociation from the multi-synthetase complex (MSC). N-terminal cleavage of KRS eventually leads to a conformational change that allows its interaction with the C-terminal PDZ binding motif of syntenin and subsequent exosome biogenesis. The KRS-syntenin complex translocates to multivesicular bodies (MVBs) that originate from endosomes involved with intraluminal vesicle (ILVs). MVBs are transporters for the secretion of cellular contents into the extracellular space. Syntenin localizes intraluminal vesicles within endosomal membranes. The KRS-syntenin complex transfers on to intraluminal vesicles in MVBs. MVBs are translocated to the plasma membrane for ILV secretion mediated by Rab family proteins. Once KRS exosomes are secreted, their membranes are eventually ruptured by proteases and KRS is released from the exosomes where it can act as an inflammatory cytokine in the extracellular space. Secreted KRS triggers macrophage/neutrophil migration and induces inflammation.
    Keywords:  caspase-8; exosome; inflammation; lysyl-tRNA synthetase; syntenin
  2. Eur J Pharmacol. 2019 Jun 13. pii: S0014-2999(19)30404-2. [Epub ahead of print]857 172452
    Chen J, Zhang M, Zhang X, Fan L, Liu P, Yu L, Cao X, Qiu S, Xu Y.
      Enhancer of zeste homolog-2 (EZH2), a histone methyltransferase, has been recognized to play a pivotal role in regulating the immune response in various diseases. However, its role in the inflammatory response induced by ischaemic stroke remains to be further investigated. The aim of this study was to determine the role of EZH2 in microglia-associated inflammation in ischaemic stroke and to further detect the effects of the EZH2 inhibitor, 3-deazaadenosine A (DZNep), in ischaemic brain injury. Here, we found that both in vivo ischemic/reperfusion (I/R) injury and in vitro oxygen-glucose deprivation (OGD) treatment induced a marked upregulation of EZH2 in microglia. The administration of the EZH2 inhibitor DZNep improved behavioural performance and reduced the infarct volume in mice after experimental stroke. Furthermore, we showed that DZNep blocked pro-inflammatory (CD86+) microglial activation and triggered anti-inflammatory (CD206+) microglial polarization in experimental stroke. Pro-inflammatory cytokines such as IL-1β, IL-6, TNF-α and CXCL10 were also significantly downregulated by DZNep. In addition, it was found that DZNep blocked the phosphorylation of signal transducer and activator of transcription 3 (STAT3) in microglia, which was increased by I/R injury and OGD. Collectively, we demonstrated that EZH2 is implicated in regulating microglial activation and exacerbates neurological deficits after ischaemic stroke, probably via activating STAT3, and that the EZH2 inhibitor DZNep can exert neuroprotective effects after ischaemic stroke.
    Keywords:  DZNep; EZH2; Inflammatory; Ischaemic stroke; Microglia
  3. Cell Stress. 2018 Nov 27. 3(1): 9-18
    Chalmin F, Bruchard M, Vegran F, Ghiringhelli F.
      Adaptive T cell immune response is essential for tumor growth control. The efficacy of immune checkpoint inhibitors is regulated by intratumoral immune response. The tumor microenvironment has a major role in adaptive immune response tuning. Tumor cells generate a particular metabolic environment in comparison to other tissues. Tumors are characterized by glycolysis, hypoxia, acidosis, amino acid depletion and fatty acid metabolism modification. Such metabolic changes promote tumor growth, impair immune response and lead to resistance to therapies. This review will detail how these modifications strongly affect CD8 and CD4 T cell functions and impact immunotherapy efficacy.
    Keywords:  T cells; acidosis; amino acids; antitumor immmunity; fatty acid; hypoxia; metabolic stress
  4. Mol Cell. 2019 Jun 10. pii: S1097-2765(19)30391-0. [Epub ahead of print]
    Lane EA, Choi DW, Garcia-Haro L, Levine ZG, Tedoldi M, Walker S, Danial NN.
      Carbohydrate response element binding protein (ChREBP) is a key transcriptional regulator of de novo lipogenesis (DNL) in response to carbohydrates and in hepatic steatosis. Mechanisms underlying nutrient modulation of ChREBP are under active investigation. Here we identify host cell factor 1 (HCF-1) as a previously unknown ChREBP-interacting protein that is enriched in liver biopsies of nonalcoholic steatohepatitis (NASH) patients. Biochemical and genetic studies show that HCF-1 is O-GlcNAcylated in response to glucose as a prerequisite for its binding to ChREBP and subsequent recruitment of OGT, ChREBP O-GlcNAcylation, and activation. The HCF-1:ChREBP complex resides at lipogenic gene promoters, where HCF-1 regulates H3K4 trimethylation to prime recruitment of the Jumonji C domain-containing histone demethylase PHF2 for epigenetic activation of these promoters. Overall, these findings define HCF-1's interaction with ChREBP as a previously unappreciated mechanism whereby glucose signals are both relayed to ChREBP and transmitted for epigenetic regulation of lipogenic genes.
    Keywords:  ChREBP; H3K4 trimethylation; HCF-1; NASH; O-GlcNAcylation; OGT; PHF2; de novo lipogenesis; glucose; hexosamine biosynthesis pathway