| First Author | Lin H | Year | 2018 |
| Journal | Proc Natl Acad Sci U S A | Volume | 115 |
| Issue | 49 | Pages | 12483-12488 |
| PubMed ID | 30442668 | Mgi Jnum | J:267641 |
| Mgi Id | MGI:6260133 | Doi | 10.1073/pnas.1806217115 |
| Citation | Lin H, et al. (2018) MARCH3 attenuates IL-1beta-triggered inflammation by mediating K48-linked polyubiquitination and degradation of IL-1RI. Proc Natl Acad Sci U S A 115(49):12483-12488 |
| abstractText | The proinflammatory cytokine IL-1beta plays critical roles in inflammatory and autoimmune diseases. IL-1beta signaling is tightly regulated to avoid excessive inflammatory response. In this study, we identified the E3 ubiquitin ligase membrane-associated RING-CH-type finger 3 (MARCH3) as a critical negative regulator of IL-1beta-triggered signaling. Overexpression of MARCH3 inhibited IL-1beta-triggered activation of NF-kappaB as well as expression of inflammatory genes, whereas MARCH3 deficiency had the opposite effects. MARCH3-deficient mice produced higher levels of serum inflammatory cytokines and were more sensitive to inflammatory death upon IL-1beta injection or Listeria monocytogenes infection. Mechanistically, MARCH3 was associated with IL-1 receptor I (IL-1RI) and mediated its K48-linked polyubiquitination at K409 and lysosomal-dependent degradation. Furthermore, IL-1beta stimulation triggered dephosphorylation of MARCH3 by CDC25A and activation of its E3 ligase activity. Our findings suggest that MARCH3-mediated IL-1RI degradation is an important mechanism for attenuating IL-1beta-triggered inflammatory response. |
