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  • TLRs were originally identified as pathogen associated


    TLRs were originally identified as pathogen-associated molecular pattern recognition receptors that recognized exogenous ligands in response to infection [31]. In cirrhotic mice or patients, the gastrointestinal tract produces and absorbs considerable bacterial LPS with increased permeability of the intestinal mucosal barrier. It is well known that TLR4 signaling plays a pivotal role in liver inflammation and fibrosis. Activation of TLR4 signaling can down-regulate the bone morphogenic protein (BMP) and activin membrane-bound inhibitor (BAMBI), which enhances TGF-β1 signaling by capturing its activated ligands and subsequent amplifies fibrogenic signaling [32,33]. Therefore, targeting TLR4 signaling pathways represents an attractive strategy for liver fibrosis treatment [34]. In this study, our data portrayed that differentially expressed KDM4D modulated TLR4 level in HSCs by modulating chromatin structure. We found that genetic silencing of Kdm4d in HSCs resulted in a significant inhibition of TLR4 signaling pathway and KDM4D promoted TLR4 transcription through its demethylation activity. Engagement of ligands with the TLR4 receptor induces activation of intracellular signaling pathways through recruitment of the receptor adaptors MyD88, resulting in activation of the IκBα kinase complex and subsequent translocation of NF-κB (p65) [24]. Consistently, the expression level of TLR4 and the phosphorylated p65 as well as the fibrotic marker α-SMA were markedly decreased in Kdm4d-deficient HSC, indicating that KDM4D is indeed indispensable for HSC activation and liver fibrogenesis in a TLR4/MyD88/NF-κB-dependent manner. Apart from NF-κB, TLR4 signal transduction cascade can stimulate c-Jun N-terminal kinase (JNK), which is also essential for HSC activation [35]. Thus, targeting KDM4D provides an alternative approach against HSC activation, further, hepatic fibrogenesis.
    Introduction Histone modifications play a crucial role in tuning many biological processes, and methylation is one of the most studied and characterized thus far [1]. This modification regulates in a dynamic way different important pathways including chromatin accessibility, transcription, DNA repair, 2578 receptor and development [2], [3], [4]. In the past decade, new researches indicate that the enzymes responsible for the modulation of histone methylation can function on non-histone substrates in different environments other than chromatin [5], [6], [7]. This concept is exemplified by LSD1/KDM1A, the first lysine demethylase discovered and, to date, one of the most studied [8], [9]. It has been shown that the non-catalytic domains within LSD1 and specific interactions with different partners determine the site-specific targeting and modulate demethylation activity, suggesting that this enzyme can also modify non-histone proteins [10], [11]. For example, the introduction of an extra four-amino acid loop following alternative splicing is involved in the switch of substrate specificity of LSD1-containing complexes from H3Lys4 to H4Lys20 [12], [13]. Similarly, it has been reported that LSD1-interacting proteins can change substrate specificity, as in the case of binding to androgen receptor and estrogen-related receptor α shown to form a demethylation complex [14], [15]. Along this line, it has also been found that transcription factors can interact with LSD1 by mimicking the H3 tail as illustrated by the SNAIL1 family [16]. These proteins bind the active site of LSD1, which is recruited to specific loci, where the demethylase becomes engaged in specific chromatin complexes to selectively modify target gene(s). It is therefore clear that the binding and catalytic properties of LSD1 active site are versatile and can be finely tuned by a number of factors, enabling the demethylase to take part in very diverse processes of cell function, differentiation, and disease. Many studies have reported that the tumour suppressor p53 is functionally associated to LSD1 for mutual regulation in the context of DNA damage response and cell death [17], [18], [19], [20]. A wealth of cellular, biochemical and structural data have dissected the functions of the different domains within p53, generating a comprehensive and detailed picture of their functions [21], [22], [23], [24]. Of relevance for this work, it has been largely reported that the role of the p53 C-terminal domain (CTD; residues 353–393 shown in Fig. 1A) is to stabilize the protein, to contribute to non-specific DNA-binding, and to recruit co-factor proteins, many being chromatin-associated such as the oncoprotein SET, p300/CBP histone acetyltransferase, and Mdm2 E3 ligase [25], [26], [27]. However, the data regarding the CTD have not yet clarified the precise function of this flexible domain, and fully reached a consensus model on how it may regulate p53 function. In this context, LSD1 was proposed to remove mono- and di-methylation on Lys370 on the CTD of p53, therefore blocking its interaction with the co-activator 53BP1 and the subsequent triggering of apoptosis in damaged cells [28]. More generally, LSD1 was also shown to be targeted to chromatin at gene-specific sites thanks to direct binding to p53, leading for example to the repression of transcription of alpha fetoprotein 2578 receptor in hepatocytes [17].