Abstract
Upon detection of viral RNA, retinoic acid-inducible gene I (RIG-I) undergoes TRIM25-mediated K63-linked ubiquitination, leading to type I interferon (IFN) production. In this study, we demonstrate that the linear ubiquitin assembly complex (LUBAC), comprised of two RING-IBR-RING (RBR)-containing E3 ligases, HOIL-1L and HOIP, independently targets TRIM25 and RIG-I to effectively suppress virus-induced IFN production. RBR E3 ligase domains of HOIL-1L and HOIP bind and induce proteasomal degradation of TRIM25, whereas the NZF domain of HOIL-1L competes with TRIM25 for RIG-I binding. Consequently, both actions by the HOIL-1L/HOIP LUBAC potently inhibit RIG-I ubiquitination and antiviral activity, but in a mechanistically separate manner. Conversely, the genetic deletion or depletion of HOIL-1L and HOIP robustly enhances virus-induced type I IFN production. Taken together, the HOIL-1L/HOIP LUBAC specifically suppresses RIG-I ubiquitination and activation by inducing TRIM25 degradation and inhibiting TRIM25 interaction with RIG-I, resulting in the comprehensive suppression of the IFN-mediated antiviral signaling pathway.
| Original language | English |
|---|---|
| Pages (from-to) | 354-365 |
| Number of pages | 12 |
| Journal | Molecular Cell |
| Volume | 41 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 4 Feb 2011 |
Bibliographical note
Funding Information:This work was partly supported by CA082057, AI083025, AI083355, KRIBB, GRL Program (K20815000001) from National Research Foundation of Korea, Hastings Foundation, and Fletcher Jones Foundation (J.U.J.) and by AI087846-01A1 and RR00168 (M.U.G.). We thank Stacy Lee for manuscript preparation and all of J.U.J.'s lab members for their discussions.