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TRAF5 negatively regulates TLR signaling in B lymphocytes.

ABSTRACT: The cytoplasmic adaptor proteins TNFR-associated factor (TRAF)3 and TRAF6 are important mediators of TLR signaling. To our knowledge, we show in this study for the first time that another TRAF family member, TRAF5, is a negative regulator of TLR signaling. B lymphocytes from TRAF5(-/-) mice produced more IL-6, IL-12p40, IL-10, TNF-?, and IgM than did wild-type B cells after TLR stimulation. Consistent with these data, exogenous overexpression of TRAF5 in B cells inhibited TLR-mediated cytokine and Ab production. TLR stimulation of TRAF5-deficient B cells did not affect cell survival, proliferation, or NF-?B activation but resulted in markedly enhanced phosphorylation of the MAPKs ERK1/2 and JNK. TRAF5 negatively regulated TLR signaling in a cell-specific manner, because TRAF5(-/-) macrophages and dendritic cells showed less dramatic differences in TLR-mediated cytokine production than B cells. Following TLR stimulation, TRAF5 associated in a complex with the TLR adaptor protein MyD88 and the B cell-specific positive regulator of TLR signaling TAB2. Furthermore, TRAF5 negatively regulated the association of TAB2 with its signaling partner TRAF6 after TLR ligation in B cells. To our knowledge, these data provide the first evidence that TRAF5 acts as a negative regulator of TLR signaling.

SUBMITTER: Buchta CM

PROVIDER: S-EPMC3872259 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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TRAF5 negatively regulates TLR signaling in B lymphocytes.

Buchta Claire M CM Bishop Gail A GA

Journal of immunology (Baltimore, Md. : 1950) 20131120 1

The cytoplasmic adaptor proteins TNFR-associated factor (TRAF)3 and TRAF6 are important mediators of TLR signaling. To our knowledge, we show in this study for the first time that another TRAF family member, TRAF5, is a negative regulator of TLR signaling. B lymphocytes from TRAF5(-/-) mice produced more IL-6, IL-12p40, IL-10, TNF-α, and IgM than did wild-type B cells after TLR stimulation. Consistent with these data, exogenous overexpression of TRAF5 in B cells inhibited TLR-mediated cytokine a ...[more]

PMID: 24259503

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Project description:Toxoplasma gondii is an important intracellular protozoan, which needs to exploit host nutrition for successful parasitism. We previously reported that Casitas B-lineage lymphoma-b (Cbl-b) was screened as a host dependency factor of T. gondii by using lentiviral CRISPR-Cas9-single guide RNA (sgRNA) libraries. Furthermore, the detailed mechanism of Cbl-b being required by T. gondii infection was explored in this study. The proliferation of T. gondii was found to be significantly inhibited in Cbl-b knockdown cell lines, and the Cbl-b expression level increased with prolonged T. gondii infection, while the MyD88 level was significantly decreased in the T. gondii infection group. Toll-like receptor (TLR)/MyD88 is a conserved innate cellular immune signaling pathway against pathogens infection. Cbl-b was found to interact with MyD88 and mediate MyD88 ubiquitination in the fluorescence resonance energy transfer and co-immunoprecipitation experiments. A Cbl-b knockout (KO) C57BL/6J lineage was then constructed and, together with the wild-type (WT) mice, was infected with the same amount of T. gondii tachyzoites of ME49 strain. At 13 days post infection, all the mice in the WT group died, while 80% of the mice in the Cbl-b KO group still survived, even to the end of the experiment. The parasitic burden in the liver, lung, and brain of the Cbl-b KO mice was significantly lower than that of the WT mice (P < 0.05). In Cbl-b KO infected mice, the percentage of B cells was higher, whereas that of macrophages was lower, and the interferon-γ and interleukin-6 levels in the serum were higher than that in the WT infected mice; the difference was significant (P < 0.05). Furthermore, when host cells were infected by T. gondii, host's Cbl-b was found to interact with MyD88 to ubiquitinate MyD88 for ribosome-dependent degradation. Therefore, the host's innate immunity against T. gondii through the TLR/MyD88 pathway was negatively regulated by Cbl-b.IMPORTANCEThis is the first report that a human E3 ubiquitin ligase, Casitas B-lineage lymphoma proto-oncogene B (Cbl-b), functions as a host dependency factor for the intracellular protozoan Toxoplasma gondii and the mechanism for how T. gondii infection inhibits the TLR/MyD88 innate immunity pathway through MyD88 degradation mediated by Cbl-b. This finding is an impactful contribution for understanding the host cell immunity against T. gondii infection.

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TRAF5 negatively regulates TLR signaling in B lymphocytes.

Publications

TRAF5 negatively regulates TLR signaling in B lymphocytes.

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