The Ubiquitin E3 Ligase RAUL Negatively Regulates Type I Interferon through Ubiquitination of the Transcription Factors IRF7 and IRF3

• Published in: Immunity (Cambridge, Mass.) Mass.), 2010-12, Vol.33 (6), p.863-877
• Main Authors: Yu, Yanxing, Hayward, Gary S.
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Cycle protein; Down-Regulation - genetics; Enzymes; Fibroblasts - immunology; Fibroblasts - metabolism; Fibroblasts - pathology; Fibroblasts - virology; Herpesviridae Infections - genetics; Herpesviridae Infections - immunology; Herpesviridae Infections - metabolism; Herpesvirus; Herpesvirus 8, Human - pathogenicity; Herpesvirus 8, Human - physiology; Humans; Immune system; Interferon Regulatory Factor-3 - metabolism; Interferon Regulatory Factor-7 - metabolism; Interferon Type I - genetics; Interferon Type I - immunology; Interferon Type I - metabolism; Mice; Mutant Proteins - genetics; Phosphorylation; Plasmids; Proteasome Endopeptidase Complex; Proteins; RNA, Small Interfering - genetics; Transcription Factors - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - immunology; Ubiquitin-Protein Ligases - metabolism; Ubiquitination - genetics; Viral infections; Virus Replication - genetics
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2010.11.027

In the course of combating infectious agents, type I interferon (IFN) needs a timely downregulation mechanism to avoid detrimental overreaction. Here we showed a mechanism for restraining type I IFN responses, which relied on a HECT domain ubiquitin (Ub) E3 ligase, RAUL. RAUL limited type I IFN production by directly catalyzing lysine 48-linked polyubiquitination of both interferon regulatory factor 7 (IRF7) and IRF3 followed by proteasome-dependent degradation. Suppression of RAUL by dominant-negative RAUL or siRNA augmented both basal and virus-induced production of type I IFN, which resulted in reduced viral replication. The Kaposi's sarcoma-associated herpes virus immediate-early lytic cycle trigger protein RTA recruited this mechanism to augment its countermeasures against the host antiviral response. These results unveil a previously unrecognized “brake mechanism” for type I IFN that maintains proper low amounts of type I IFN under physiological conditions and restrains its magnitude when the antiviral response intensifies. ► Ub ligase RAUL limits type I IFN by catalyzing K48 ubiquitination of IRF7 and IRF3 ► Suppression of RAUL augments production of type I IFN and reduces viral replication ► RAUL activity is positively regulated by deubiquitinase Usp7 ► Virus KSHV RTA recruits the Usp 7-RAUL mechanism to antagonize antiviral responses