Dataset Information

TRIM38 inhibits TNF?- and IL-1?-triggered NF-?B activation by mediating lysosome-dependent degradation of TAB2/3.

ABSTRACT: TNF? and IL-1? are two proinflammatory cytokines that play critical roles in many diseases, including rheumatoid arthritis and infectious diseases. How TNF?- and IL-1?-mediated signaling is finely tuned is not fully elucidated. Here, we identify tripartite-motif protein 38 (TRIM38) as a critical negative regulator of TNF?- and IL-1?-triggered signaling. Overexpression of TRIM38 inhibited activation of NF-?B and induction of downstream cytokines following TNF? and IL-1? stimulation, whereas knockdown or knockout of TRIM38 had the opposite effects. TRIM38 constitutively interacted with critical components TGF-?-activated kinase 1 (TAK1)-binding protein 2/3 (TAB2/3) and promoted lysosome-dependent degradation of TAB2/3 independent of its E3 ubiquitin ligase activity. Consistently, deficiency of TRIM38 resulted in abolished translocation of TAB2 to the lysosome, increased level of TAB2 in cells, and enhanced activation of TAK1 after TNF? and IL-1? stimulation. We conclude that TRIM38 negatively regulates TNF?- and IL-1?-induced signaling by mediating lysosome-dependent degradation of TAB2/3, two critical components in TNF?- and IL-1?-induced signaling pathways. Our findings reveal a previously undiscovered mechanism by which cells keep the inflammatory response in check to avoid excessive harmful immune response triggered by TNF? and IL-1?.

SUBMITTER: Hu MM

PROVIDER: S-EPMC3910612 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

TRIM38 inhibits TNFα- and IL-1β-triggered NF-κB activation by mediating lysosome-dependent degradation of TAB2/3.

Hu Ming-Ming MM Yang Qing Q Zhang Jing J Liu Shi-Meng SM Zhang Yu Y Lin Heng H Huang Zhe-Fu ZF Wang Yan-Yi YY Zhang Xiao-Dong XD Zhong Bo B Shu Hong-Bing HB

Proceedings of the National Academy of Sciences of the United States of America 20140113 4

TNFα and IL-1β are two proinflammatory cytokines that play critical roles in many diseases, including rheumatoid arthritis and infectious diseases. How TNFα- and IL-1β-mediated signaling is finely tuned is not fully elucidated. Here, we identify tripartite-motif protein 38 (TRIM38) as a critical negative regulator of TNFα- and IL-1β-triggered signaling. Overexpression of TRIM38 inhibited activation of NF-κB and induction of downstream cytokines following TNFα and IL-1β stimulation, whereas knock ...[more]

PMID: 24434549

Similar Datasets

Project description:IntroductionMesenchymal stem cells (MSCs) have the ability to repair and regenerate tissue, home to sites of inflammation, and evade the host immune system. As such, they represent an attractive therapy for the treatment of autoimmune inflammatory diseases. However, results from in vivo murine studies in inflammatory arthritis have been conflicting, and this may be due to the genetic background of the MSCs used. It is known that the inflammatory milieu may influence properties of MSCs and that, in the case of human bone marrow-derived MSCs, this may be mediated by the nuclear factor-kappa-B (NF-κB) pathway. We sought to determine whether pro-inflammatory cytokines altered the differentiation and migration capacity of murine MSCs from different mouse strains and whether this was mediated by NF-κB.MethodsThe differentiation and migration of FVB and BALB/c MSCs were carried out in the presence of varying concentrations of tumor necrosis factor-alpha (TNFα) and interleukin (IL)-1β, and the NF-κB pathway was inhibited in one of two ways: either by transduction of MSCs with an adenoviral vector expressing a super-repressor of NF-κB or by the addition of curcumin to culture media.ResultsBoth BALB/c and FVB MSCs were sensitive to the effect of pro-inflammatory cytokines in vitro. TNFα and IL-1β suppressed BALB/c osteogenesis and adipogenesis and FVB osteogenesis. The migration of both cell types toward media containing fetal bovine serum was augmented by pre-stimulation with either cytokine. In neither cell type were the cytokine effects reversed by abrogation of the NF-κB pathway.ConclusionsThese data show that murine MSCs from different genetic backgrounds may be influenced by an inflammatory milieu in a manner that is not mediated by NF-κB, as is the case for human MSCs. This is not mediated by NF-κB. These findings are important and should influence how in vivo trials of murine MSCs are interpreted and the future development of pre-clinical studies in inflammatory diseases.

Dataset Information

TRIM38 inhibits TNF?- and IL-1?-triggered NF-?B activation by mediating lysosome-dependent degradation of TAB2/3.

Publications

TRIM38 inhibits TNFα- and IL-1β-triggered NF-κB activation by mediating lysosome-dependent degradation of TAB2/3.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets