Dataset Information

Mycobacterial PPE36 Modulates Host Inflammation by Promoting E3 Ligase Smurf1-Mediated MyD88 Degradation.

ABSTRACT: Mycobacterium tuberculosis (Mtb) PPE36, a cell-wall-associated protein, is highly specific and conserved for the Mtb complex group. Although PPE36 has been proven essential for iron utilization, little is known about it in regulating host immune responses. Here we exhibited that PPE36 was preferentially enriched in Mtb virulent strains and could efficiently inhibit host inflammatory responses and increase bacterial loads in infected macrophages and mice. In exploring the underlying mechanisms, we found that PPE36 could robustly inhibit the activation of inflammatory NF-κB and MAPK (Erk, p38, and Jnk) pathways by promoting E3 ligase Smurf1-mediated ubiquitination and proteasomal degradation of MyD88 protein. Our research revealed a previously unknown function of PPE36 on modulating host immune responses and provided some clues to the development of novel tuberculosis treatment strategies based on immune regulation.

SUBMITTER: Peng Z

PROVIDER: S-EPMC8882603 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

<i>Mycobacterial</i> PPE36 Modulates Host Inflammation by Promoting E3 Ligase Smurf1-Mediated MyD88 Degradation.

Peng Zhangli Z Yue Yan Y Xiong Sidong S

Frontiers in immunology 20220214

<i>Mycobacterium tuberculosis</i> (Mtb) PPE36, a cell-wall-associated protein, is highly specific and conserved for the Mtb complex group. Although PPE36 has been proven essential for iron utilization, little is known about it in regulating host immune responses. Here we exhibited that PPE36 was preferentially enriched in Mtb virulent strains and could efficiently inhibit host inflammatory responses and increase bacterial loads in infected macrophages and mice. In exploring the underlying mechan ...[more]

PMID: 35237255

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Project description:BackgroundSubstance use disorder is a neurobiological disease characterized by episodes of relapse despite periods of withdrawal. It is thought that neuroadaptations in discrete brain areas of the reward pathway, including the nucleus accumbens, underlie these aberrant behaviors. The ubiquitin-proteasome system degrades proteins and has been shown to be involved in cocaine-induced plasticity, but the role of E3 ubiquitin ligases, which conjugate ubiquitin to substrates, is unknown. Here, we examined E3 ubiquitin-protein ligase SMURF1 (SMURF1) in neuroadaptations and relapse behavior during withdrawal following cocaine self-administration.MethodsSMURF1 and downstream targets ras homolog gene family, member A (RhoA), SMAD1/5, and Runt-related transcript factor 2 were examined using Western blotting (n = 9-11/group), quantitative polymerase chain reaction (n = 6-9/group), co-immunoprecipitation (n = 9-11/group), tandem ubiquitin binding entities affinity purification (n = 5-6/group), and quantitative chromatin immunoprecipitation (n = 3-6/group) (2 rats/sample). Viral-mediated gene transfer (n = 7-12/group) and intra-accumbal microinjections (n = 9-10/group) were used to examine causal roles of SMURF1 and substrate RhoA, respectively, in cue-induced cocaine seeking.ResultsSMURF1 protein expression was decreased, while SMURF1 substrates RhoA and SMAD1/5 were increased, in the nucleus accumbens on withdrawal day 7, but not on withdrawal day 1, following cocaine self-administration. Viral-mediated gene transfer of Smurf1 or constitutive activation of RhoA attenuated cue-induced cocaine seeking, while catalytically inactive Smurf1 enhanced cocaine seeking. Furthermore, SMURF1-regulated, SMAD1/5-associated transcription factor Runt-related transcript factor 2 displayed increased binding at promoter regions of genes previously associated with cocaine-induced plasticity.ConclusionsSMURF1 is a key mediator of neuroadaptations in the nucleus accumbens following cocaine exposure and mediates cue-induced cocaine seeking during withdrawal.

Dataset Information

Mycobacterial PPE36 Modulates Host Inflammation by Promoting E3 Ligase Smurf1-Mediated MyD88 Degradation.

Publications

<i>Mycobacterial</i> PPE36 Modulates Host Inflammation by Promoting E3 Ligase Smurf1-Mediated MyD88 Degradation.

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