Epigenetic regulation of
            <i>Kcna3</i>
            -encoding Kv1.3 potassium channel by cereblon contributes to regulation of CD4
            <sup>+</sup>
            T-cell activation

Kang, Jung‐Ah; Park, Sangheon; Jeong, Sang Phil; Han, Minhee; Lee, Cho-Rong; Lee, Kwang Min; Kim, Namhee; Song, Mi-Ryoung; Choi, Murim; Ye, Michael; Jung, Gyuweon; Lee, Won Woo; Eom, Soo Hyun; Park, Chul–Seung; Park, Sung‐Gyoo

doi:10.1073/pnas.1502166113

Cited by 36 publications

(34 citation statements)

References 23 publications

(27 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These functions are achieved through the regulation of protein-DNA or protein-protein interaction, which further affects downstream signaling pathways. For example, CRBN epigenetically suppresses the expression of the Kv1.3 potassium channel by its binding to the conserved DNA elements adjacent to the Kcna3 gene, thus limiting T cell activation and IL-2 production upon T cell receptor stimulation (49). CRBN also exhibits a chaperone-like function that promotes maturation of CD147 and MCT1 and activation of the CD147-MCT1 transmembrane complex.…”

Section: Discussionmentioning

confidence: 99%

Cereblon suppresses the lipopolysaccharide-induced inflammatory response by promoting the ubiquitination and degradation of c-Jun

Yang

Huang

Zhou

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

Chronic inflammation is associated with multiple human disorders such as rheumatoid arthritis, metabolic diseases, and neurodegenerative diseases. Therefore, alleviation of inflammation induced by environment stimuli is important for disease prevention or treatment. Cereblon (CRBN) functions as a substrate receptor of the cullin-4 RING E3 ligase to mediate protein ubiquitination and degradation. Although it has been reported that CRBN reduces the inflammatory response through its non-enzymatic function, its role as a substrate receptor of the E3 ligase is not explored in mediating this process. Here, we use quantitative proteomic approach to find that the major component of the activator protein 1 (AP-1) complex, c-Jun, is significantly down-regulated upon CRBN expression. Biochemical approaches further discover that CRBN interacts and partially colocalizes with c-Jun, promotes the formation of the K48-linked polyubiquitin chains on c-Jun, and thus enhances c-Jun degradation. We further reveal that CRBN attenuates the transcriptional activity of AP-1 complex and reduces the mRNA expression and protein level of several pro-inflammatory cytokines. Moreover, flow cytometry analyses show that CRBN attenuates the lipopolysaccharide (LPS)-induced apoptosis in the differentiated THP-1 cells. Through genetic manipulation and pharmacological inhibition, we uncover a new molecular mechanism by which CRBN regulates the inflammatory response and apoptosis induced by LPS. Our work and previous studies demonstrate that CRBN suppresses the inflammatory response by promoting or inhibiting the ubiquitination of two key molecules at different levels of the inflammatory cascade through the enzymatic function as a substrate receptor and the non-enzymatic function as a protein binding partner.

show abstract

Section: Discussionmentioning

confidence: 99%

Cereblon suppresses the lipopolysaccharide-induced inflammatory response by promoting the ubiquitination and degradation of c-Jun

Yang

Huang

Zhou

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Two other HGS genes-CRBN and UBAP2 -are involved in ubiquitination. CRBN, which is highly expressed in CD4+ T-cells, forms a complex with E3 ubiquitin ligase and regulates sensitivity to TCR stimulation [42]. UBAP2 codifies an ubiquitin associated domain-containing protein (UBA) acting in the ubiquitin-dependent proteasomal degradation [43], a pathway involved in relevant thymic functions, such as the generation of MHC class I ligands [44].…”

Section: Weighted Gene Co-expression Network Analysis (Wgcna)mentioning

confidence: 99%

Age-related transcriptional modules and TF-miRNA-mRNA interactions in neonatal and infant human thymus

et al. 2020

View full text Add to dashboard Cite

The human thymus suffers a transient neonatal involution, recovers and then starts a process of decline between the 1 st and 2 nd years of life. Age-related morphological changes in thymus were extensively investigated, but the genomic mechanisms underlying this process remain largely unknown. Through Weighted Gene Co-expression Network Analysis (WGCNA) and TF-miRNA-mRNA integrative analysis we studied the transcriptome of neonate and infant thymic tissues grouped by age: 0-30 days (A); 31days-6 months (B); 7-12 months (C); 13-18 months (D); 19-31months (E). Age-related transcriptional modules, hubs and high gene significance (HGS) genes were identified, as well as TF-miRNA-hub/HGS co-expression correlations. Three transcriptional modules were correlated with A and/or E groups. Hubs were mostly related to cellular/metabolic processes; few were differentially expressed (DE) or related to T-cell development. Inversely, HGS genes in groups A and E were mostly DE. In A (neonate) one third of the hyper-expressed HGS genes were related to T-cell development, against one-twentieth in E, what may correlate with the early neonatal depletion and recovery of thymic T-cell populations. This genomic mechanism is tightly regulated by TF-miRNA-hub/HGS interactions that differentially govern cellular and molecular processes involved in the functioning of the neonate thymus and in the beginning of thymic decline.

show abstract

“…For measurement of secreted cytokine levels, lymphocytes were isolated from the lymph nodes of CIA mice. Isolated lymphocytes (1 × 10 6 ) were cultured for 4 h with PMA (50 ng/ml) and ionomycin (500 ng/ml) [ 24 ]. The LEGEND MAX mouse IL-6 ELISA kit and mouse IL-13 Platinum ELISA kit (Invitrogen) were used to detect IL-6 and IL-10, respectively.…”

Section: Methodsmentioning

confidence: 99%

BATF regulates collagen-induced arthritis by regulating T helper cell differentiation

et al. 2018

Self Cite

View full text Add to dashboard Cite

BackgroundWe recently demonstrated that BATF, a member of the activator protein-1 (AP-1) family, regulates osteoarthritic cartilage destruction. Here, we explored the roles and regulatory mechanisms of BATF in collagen-induced arthritis (CIA) in mice.MethodsCIA and K/BxN serum transfer were used to generate inflammatory arthritis models in wild-type (WT) and Batf−/− mice. RA manifestations were determined by examining CIA incidence, clinical score, synovitis, synovial hyperplasia, angiogenesis in inflamed synovium, pannus formation, bone erosion, and cartilage destruction. Immune features in RA were analyzed by examining immune cell populations and cytokine production.ResultsBATF was upregulated in the synovial tissues of joints in which inflammatory arthritis had been caused by CIA or K/BxN serum transfer. The increases in CIA incidence, clinical score, and autoantibody production in CIA-induced WT mice were completely abrogated in the corresponding Batf−/− DBA/1 J mice. Genetic ablation of Batf also inhibited CIA-induced synovitis, synovial hyperplasia, angiogenesis in synovial tissues, pannus formation, bone erosion, and cartilage destruction. Batf knockout inhibited the differentiation of T helper (Th)17 cells and the conversion of CD4+Foxp3+ cells to CD4+IL-17+ cells. However, BATF did not modulate the functions of fibroblast-like synoviocytes (FLS), including the expressions of chemokines, matrix-degrading enzymes, vascular endothelial growth factor, and receptor activator of NF-κB ligand (RANKL).ConclusionOur findings indicate that BATF crucially mediates CIA by regulating Th cell differentiation without directly affecting the functions of FLS.

show abstract

Epigenetic regulation of Kcna3 -encoding Kv1.3 potassium channel by cereblon contributes to regulation of CD4 ⁺ T-cell activation

Cited by 36 publications

References 23 publications

Cereblon suppresses the lipopolysaccharide-induced inflammatory response by promoting the ubiquitination and degradation of c-Jun

Cereblon suppresses the lipopolysaccharide-induced inflammatory response by promoting the ubiquitination and degradation of c-Jun

Age-related transcriptional modules and TF-miRNA-mRNA interactions in neonatal and infant human thymus

BATF regulates collagen-induced arthritis by regulating T helper cell differentiation

Contact Info

Product

Resources

About

Epigenetic regulation of Kcna3 -encoding Kv1.3 potassium channel by cereblon contributes to regulation of CD4 + T-cell activation

Cited by 36 publications

References 23 publications

Cereblon suppresses the lipopolysaccharide-induced inflammatory response by promoting the ubiquitination and degradation of c-Jun

Cereblon suppresses the lipopolysaccharide-induced inflammatory response by promoting the ubiquitination and degradation of c-Jun

Age-related transcriptional modules and TF-miRNA-mRNA interactions in neonatal and infant human thymus

BATF regulates collagen-induced arthritis by regulating T helper cell differentiation

Contact Info

Product

Resources

About

Epigenetic regulation of Kcna3 -encoding Kv1.3 potassium channel by cereblon contributes to regulation of CD4 ⁺ T-cell activation