| First Author | Lu Y | Year | 2019 |
| Journal | Nat Microbiol | Volume | 4 |
| Issue | 12 | Pages | 2331-2346 |
| PubMed ID | 31477895 | Mgi Jnum | J:293367 |
| Mgi Id | MGI:6452731 | Doi | 10.1038/s41564-019-0542-2 |
| Citation | Lu Y, et al. (2019) ER-localized Hrd1 ubiquitinates and inactivates Usp15 to promote TLR4-induced inflammation during bacterial infection. Nat Microbiol 4(12):2331-2346 |
| abstractText | The special organelle-located MAVS, STING and TLR3 are important for clearing viral infections. Although TLR4 triggers NF-kappaB activation to produce pro-inflammatory cytokines for bacterial clearance, effectors with special organelle localization have not been identified. Here, we screened more than 280 E3 ubiquitin ligases and discovered that the endoplasmic reticulum-located Hrd1 regulates TLR4-induced inflammation during bacterial infection. Hrd1 interacts directly with the deubiquitinating enzyme Usp15. Unlike the classical function of Hrd1 in endoplasmic reticulum-associated degradation, Usp15 is not degraded but loses its deubiquitinating activity for IkappaBalpha deubiquitination, resulting in excessive NF-kappaB activation. Importantly, Hrd1 deficiency in macrophages protects mice against lipopolysaccharide-induced septic shock, and knockdown of Usp15 in Hrd1-knockout macrophages restores the reduced IL-6 production. This study proposes that there is crosstalk between Hrd1 and TLR4, thereby linking the endoplasmic reticulum-plasma membrane function during bacterial infection. |
