DDIT4 S‐Nitrosylation Aids p38‐MAPK Signaling Complex Assembly to Promote Hepatic Reactive Oxygen Species Production

Abstract

Mitogen-activated protein kinase (MAPK) signaling plays a significant role in reactive oxygen species (ROS) production. The authors have previously shown that Brahma-related gene 1 (BRG1), a chromatin remodeling protein, contributes to hepatic ROS accumulation in multiple animal and cellular models of liver injury. Here it is reported that DNA damage-induced transcript 4 (DDIT4) is identified as a direct transcriptional target for BRG1. DDIT4 overexpression overcomes BRG1 deficiency to restore ROS production whereas DDIT4 knockdown phenocopies BRG1 deficiency in suppressing ROS production in vitro and in vivo. Mechanistically, DDIT4 coordinates the assembly of the p38-MAPK signaling complex to drive ROS production in an S-nitrosylation dependent manner. Molecular docking identifies several bioactive DDIT4-inteacting compounds including imatinib, nilotinib, and nateglinide, all of which are confirmed to attenuate hepatic ROS production, dampen p38-MAPK signaling, and ameliorate liver injury by influencing DDIT4 S-nitrosylation. Importantly, positive correlation between ROS levels and BRG1/DDIT4/S-nitrosylated DDIT4 levels is detected in human liver biopsy specimens. In conclusion, the data reveal a transcription-based signaling cascade that contributes to ROS production in liver injury.

Identification and Validation of Dilated Cardiomyopathy-Related Genes via Bioinformatics Analysis

“… 47 In addition to cardiac diseases, relevant studies in other diseases have shown that DDIT4 mediates the apoptotic process, for example, Lynn M Knowles et al verified that increasing DDIT4 induces caspase-8 mediated tumor cell apoptosis via negatively regulating the mTOR signaling pathway. 48 And Li revealed that DDIT4 can promote the production of ROS in liver injury, 49 which suggests that the expression of DDIT4 is related to the injury of cells. The detailed functional mechanisms of DDIT4 in DCM remain unclear.…”

Down-Regulation of CXXC5 De-Represses MYCL1 to Promote Hepatic Stellate Cell Activation

“…All the animal experiments were reviewed and approved by the Nanjing Medical University Ethics Committee on Humane Treatment of Laboratory Animals. To induce liver fibrosis, male C57BL/6 mice were injected with CCl 4 (1.0 mL/kg as 50% vol/vol) or subjected to bile duct ligation (BDL) as previously described ( Wang Q. et al, 2020 ; Li et al, 2021 ). Picrosirius red staining was performed with paraffin-embedded liver sections using a commercially available kit (Sigma Aldrich) as previously described ( Li et al, 2021 ).…”

“…To induce liver fibrosis, male C57BL/6 mice were injected with CCl 4 (1.0 mL/kg as 50% vol/vol) or subjected to bile duct ligation (BDL) as previously described ( Wang Q. et al, 2020 ; Li et al, 2021 ). Picrosirius red staining was performed with paraffin-embedded liver sections using a commercially available kit (Sigma Aldrich) as previously described ( Li et al, 2021 ). For hydroxylproline quantification, ∼10 mg of liver tissue was weighed, homogenized, and hydrolyzed in HCl (10N) at 120°C for 3 h. Supernatants were transferred to a 96-well plate and hydroxylproline content was determined by colorimetry (Sigma Aldrich, MAK008).…”

An E2F5-TFDP1-BRG1 Complex Mediates Transcriptional Activation of MYCN in Hepatocytes

“…Histological analyses were performed essentially as described before (Li et al, 2021). Paraffin sections were stained with were blocked with 10% normal goat serum for 1 h at room temperature and then incubated with anti-MYCN (Proteinch, 1:200) or anti-PCNA (Abcam, 1:200) antibodies.…”