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Peli1 facilitates TRIF-dependent Toll-like receptor signaling and proinflammatory cytokine production.

Chang M, Jin W, Sun SC - Nat. Immunol. (2009)

Bottom Line: Peli1 was required for TLR3-induced activation of IkappaB kinase (IKK) and its 'downstream' target, transcription factor NF-kappaB, but was dispensable for IKK-NF-kappaB activation induced by several other TLRs and the interleukin 1 (IL-1) receptor.Notably, Peli1 bound to and ubiquitinated RIP1, a signaling molecule that mediates IKK activation induced by the TLR3 and TLR4 adaptor TRIF.Our findings suggest that Peli1 is a ubiquitin ligase needed for the transmission of TRIF-dependent TLR signals.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

ABSTRACT
Toll-like receptors (TLRs) are pivotal in innate immunity and inflammation. Here we show that genetic deficiency in Peli1, an E3 ubiquitin ligase, attenuated the induction of proinflammatory cytokines by ligands of TLR3 and TLR4 and rendered mice resistant to septic shock. Peli1 was required for TLR3-induced activation of IkappaB kinase (IKK) and its 'downstream' target, transcription factor NF-kappaB, but was dispensable for IKK-NF-kappaB activation induced by several other TLRs and the interleukin 1 (IL-1) receptor. Notably, Peli1 bound to and ubiquitinated RIP1, a signaling molecule that mediates IKK activation induced by the TLR3 and TLR4 adaptor TRIF. Our findings suggest that Peli1 is a ubiquitin ligase needed for the transmission of TRIF-dependent TLR signals.

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Peli1−/− mice are resistant to LPS- and poly(I:C)-induced lethality(a,b) Age- and sex-matched Peli1+/+ and Peli1−/− mice (8 week old; 5 Peli1+/+ and 5 Peli1−/− for a; 6 Peli1+/+ and 5 Peli1−/− for b) were injected (i.p.) with LPS plus D-galactosamine (a) or poly(I:C) plus D-galactosamine (b). Lethality was monitored every hour for 24 hours. (c) Mice shown in a were bled at the indicated times after injection, and the serum concentration of the indicated cytokines was determined by ELISA and presented as mean ± s.d. (d) Mice shown in b were bled at the indicated times after injection, and the serum concentration of the indicated cytokines was determined by ELISA and presented as mean ± sd. * P < 0.05 and ** P < 0.01. Data are representative of 3 independent experiments with similar results.
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Figure 1: Peli1−/− mice are resistant to LPS- and poly(I:C)-induced lethality(a,b) Age- and sex-matched Peli1+/+ and Peli1−/− mice (8 week old; 5 Peli1+/+ and 5 Peli1−/− for a; 6 Peli1+/+ and 5 Peli1−/− for b) were injected (i.p.) with LPS plus D-galactosamine (a) or poly(I:C) plus D-galactosamine (b). Lethality was monitored every hour for 24 hours. (c) Mice shown in a were bled at the indicated times after injection, and the serum concentration of the indicated cytokines was determined by ELISA and presented as mean ± s.d. (d) Mice shown in b were bled at the indicated times after injection, and the serum concentration of the indicated cytokines was determined by ELISA and presented as mean ± sd. * P < 0.05 and ** P < 0.01. Data are representative of 3 independent experiments with similar results.

Mentions: To investigate the in vivo function of Peli1 in regulating TLR signaling, we employed a septic shock model involving intra-peritoneal (i.p.) injection of the TLR4 ligand LPS plus a liver-specific transcription inhibitor, D-galactosamine, which enhances the toxicity of LPS 24. In this acute inflammation model, lethality occurs within hours and is largely dependent on the production of the proinflammatory cytokine TNF 25, 26. As expected, injection of LPS and D-galacosamine caused lethality in the majority of Peli1+/+ mice within 9 hours and killed all of them within 18 hours (Fig. 1a). In sharp contrast, none of the Peli1−/− mice succumbed to the septic shock induction during the entire 24 hour time period (Fig. 1a). We also employed a septic shock model involving injection of high-doses of LPS in the absence of D-galactosamine. As expected, a much higher dose of LPS (45 mg/kg body weight) and a considerably longer time (24 hours) were required to induce a moderate frequency (2 out of 6) of lethality in wild-type mice (Supplementary Fig. 3). At this time, none of the Peli1−/− mice succumbed. After longer times, 1 of the 6 Peli1−/− mice died, compared to 50% of the Peli1+/+ mice (Supplementary Fig. 3). Thus, although less striking than the acute lethality model, the Peli1 deficiency also caused reduced the lethality induced in the high-dose LPS model.


Peli1 facilitates TRIF-dependent Toll-like receptor signaling and proinflammatory cytokine production.

Chang M, Jin W, Sun SC - Nat. Immunol. (2009)

Peli1−/− mice are resistant to LPS- and poly(I:C)-induced lethality(a,b) Age- and sex-matched Peli1+/+ and Peli1−/− mice (8 week old; 5 Peli1+/+ and 5 Peli1−/− for a; 6 Peli1+/+ and 5 Peli1−/− for b) were injected (i.p.) with LPS plus D-galactosamine (a) or poly(I:C) plus D-galactosamine (b). Lethality was monitored every hour for 24 hours. (c) Mice shown in a were bled at the indicated times after injection, and the serum concentration of the indicated cytokines was determined by ELISA and presented as mean ± s.d. (d) Mice shown in b were bled at the indicated times after injection, and the serum concentration of the indicated cytokines was determined by ELISA and presented as mean ± sd. * P < 0.05 and ** P < 0.01. Data are representative of 3 independent experiments with similar results.
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Figure 1: Peli1−/− mice are resistant to LPS- and poly(I:C)-induced lethality(a,b) Age- and sex-matched Peli1+/+ and Peli1−/− mice (8 week old; 5 Peli1+/+ and 5 Peli1−/− for a; 6 Peli1+/+ and 5 Peli1−/− for b) were injected (i.p.) with LPS plus D-galactosamine (a) or poly(I:C) plus D-galactosamine (b). Lethality was monitored every hour for 24 hours. (c) Mice shown in a were bled at the indicated times after injection, and the serum concentration of the indicated cytokines was determined by ELISA and presented as mean ± s.d. (d) Mice shown in b were bled at the indicated times after injection, and the serum concentration of the indicated cytokines was determined by ELISA and presented as mean ± sd. * P < 0.05 and ** P < 0.01. Data are representative of 3 independent experiments with similar results.
Mentions: To investigate the in vivo function of Peli1 in regulating TLR signaling, we employed a septic shock model involving intra-peritoneal (i.p.) injection of the TLR4 ligand LPS plus a liver-specific transcription inhibitor, D-galactosamine, which enhances the toxicity of LPS 24. In this acute inflammation model, lethality occurs within hours and is largely dependent on the production of the proinflammatory cytokine TNF 25, 26. As expected, injection of LPS and D-galacosamine caused lethality in the majority of Peli1+/+ mice within 9 hours and killed all of them within 18 hours (Fig. 1a). In sharp contrast, none of the Peli1−/− mice succumbed to the septic shock induction during the entire 24 hour time period (Fig. 1a). We also employed a septic shock model involving injection of high-doses of LPS in the absence of D-galactosamine. As expected, a much higher dose of LPS (45 mg/kg body weight) and a considerably longer time (24 hours) were required to induce a moderate frequency (2 out of 6) of lethality in wild-type mice (Supplementary Fig. 3). At this time, none of the Peli1−/− mice succumbed. After longer times, 1 of the 6 Peli1−/− mice died, compared to 50% of the Peli1+/+ mice (Supplementary Fig. 3). Thus, although less striking than the acute lethality model, the Peli1 deficiency also caused reduced the lethality induced in the high-dose LPS model.

Bottom Line: Peli1 was required for TLR3-induced activation of IkappaB kinase (IKK) and its 'downstream' target, transcription factor NF-kappaB, but was dispensable for IKK-NF-kappaB activation induced by several other TLRs and the interleukin 1 (IL-1) receptor.Notably, Peli1 bound to and ubiquitinated RIP1, a signaling molecule that mediates IKK activation induced by the TLR3 and TLR4 adaptor TRIF.Our findings suggest that Peli1 is a ubiquitin ligase needed for the transmission of TRIF-dependent TLR signals.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

ABSTRACT
Toll-like receptors (TLRs) are pivotal in innate immunity and inflammation. Here we show that genetic deficiency in Peli1, an E3 ubiquitin ligase, attenuated the induction of proinflammatory cytokines by ligands of TLR3 and TLR4 and rendered mice resistant to septic shock. Peli1 was required for TLR3-induced activation of IkappaB kinase (IKK) and its 'downstream' target, transcription factor NF-kappaB, but was dispensable for IKK-NF-kappaB activation induced by several other TLRs and the interleukin 1 (IL-1) receptor. Notably, Peli1 bound to and ubiquitinated RIP1, a signaling molecule that mediates IKK activation induced by the TLR3 and TLR4 adaptor TRIF. Our findings suggest that Peli1 is a ubiquitin ligase needed for the transmission of TRIF-dependent TLR signals.

Show MeSH
Related in: MedlinePlus