USP38 Couples Histone Ubiquitination and Methylation via KDM5B to Resolve Inflammation

Abstract

Chromatin modifications, such as histone acetylation, ubiquitination, and methylation, play fundamental roles in maintaining chromatin architecture and regulating gene transcription. Although their crosstalk in chromatin remodeling has been gradually uncovered, the functional relationship between histone ubiquitination and methylation in regulating immunity and inflammation remains unclear. Here, it is reported that USP38 is a novel histone deubiquitinase that works together with the histone H3K4 modifier KDM5B to orchestrate inflammatory responses. USP38 specifically removes the monoubiquitin on H2B at lysine 120, which functions as a prerequisite for the subsequent recruitment of demethylase KDM5B to the promoters of proinflammatory cytokines Il6 and Il23a during LPS stimulation. KDM5B in turn inhibits the binding of NF-B transcription factors to the Il6 and Il23a promoters by reducing H3K4 trimethylation. Furthermore, USP38 can bind to KDM5B and prevent it from proteasomal degradation, which further enhances the function of KDM5B in the regulation of inflammation-related genes. Loss of Usp38 in mice markedly enhances susceptibility to endotoxin shock and acute colitis, and these mice display a more severe inflammatory phenotype compared to wild-type mice. The studies identify USP38-KDM5B as a distinct chromatin modification complex that restrains inflammatory responses through manipulating the crosstalk of histone ubiquitination and methylation.

A KDM4-DBC1-SIRT1 Axis Contributes to TGF-b Induced Mesenchymal Transition of Intestinal Epithelial Cells

“…Chromatin Immunoprecipitation (ChIP) assays were performed essentially as described before ( Coarfa et al, 2020 ; Hu et al, 2020 ; Jehanno et al, 2020 ; Maity et al, 2020 ; Mallik et al, 2020 ; Moon et al, 2020 ; Shen et al, 2020 ; Wang J. N. et al, 2020 ; Wang S. et al, 2020 ; Zhang et al, 2020 ; Zhao et al, 2020 ; Marti et al, 2021 ; Peng et al, 2021 ; Rashid et al, 2021 ). In brief, chromatin in control and treated cells were cross-linked with 1% formaldehyde.…”

Choline Kinase Alpha Is a Novel Transcriptional Target of the Brg1 in Hepatocyte: Implication in Liver Regeneration

“…Chromatin immunoprecipitation (ChIP) assays were performed essentially as described before (Coarfa et al, 2020;Hu et al, 2020;Jehanno et al, 2020;Maity et al, 2020;Mallik et al, 2020;Moon et al, 2020;Shen et al, 2020;Wang et al, 2020a,b;Zhang et al, 2020;Zhao et al, 2020;Marti et al, 2021;Peng et al, 2021;Rashid et al, 2021). In brief, chromatin in control and treated cells were cross-linked with 1% formaldehyde.…”

The Role of E3 Ubiquitin Ligases and Deubiquitinases in Inflammatory Bowel Disease: Friend or Foe?

“…Subsequently, specific knockout UPS22 in IECs increased the severity of inflammation in mice with DSS colitis and promoted colitis-related colorectal cancer, further confirming the role of USP22 in repressing intestinal inflammation and tumors ( 143 ). Finally, a recent study found an increased susceptibility to DSS-induced colitis in USP38 KO mice, accompanied by higher levels of IL-6 and IL-23A in colon tissue and peripheral blood ( 144 ). Mechanistic studies uncovered a role for USP38 in stabilizing the lysine demethylase 5B (KDM5B) by removing the K48-linked polyubiquitin chains, thus promoting KDM5B-mediated histone demethylation to inhibit the expression of IL-6 and IL-23A in bone marrow-derived cells, and ultimately inhibiting the occurrence and progression of intestinal inflammation ( 144 ).…”