Linear Ubiquitination of NEMO Negatively Regulates the Interferon Antiviral Response through Disruption of the MAVS-TRAF3 Complex

Abstract

The RIG-I/Mda5 sensors recognize viral intracellular RNA and trigger host antiviral responses. RIG-I signals through the adaptor protein MAVS, which engages various TRAF family members and results in type I interferon (IFNs) and proinflammatory cytokine production via activation of IRFs and NF-κB, respectively. Both the IRF and NF-κB pathways also require the adaptor protein NEMO. We determined that the RIG-I pathway is differentially regulated by the linear ubiquitin assembly complex (LUBAC), which consists of the E3 ligases HOIL-1L, HOIP, and the accessory protein SHARPIN. LUBAC downregulated virus-mediated IFN induction by targeting NEMO for linear ubiquitination. Linear ubiquitinated NEMO associated with TRAF3 and disrupted the MAVS-TRAF3 complex, which inhibited IFN activation while stimulating NF-κB-dependent signaling. In SHARPIN-deficient MEFs, vesicular stomatitis virus replication was decreased due to increased IFN production. Linear ubiquitination thus switches NEMO from a positive to a negative regulator of RIG-I signaling, resulting in an attenuated IFN response.

Hantavirus GnT Elements Mediate TRAF3 Binding and Inhibit RIG-I/TBK1-Directed Beta Interferon Transcription by Blocking IRF3 Phosphorylation

“…TRAF3 is an E3 ligase that normally directs the constitutive degradation of the NF-B inducer NIK and forms complexes with TRAF2-cIAP or ORUD7B that regulate NF-B and TBK1/IKKε activation (27, 34-36, 38, 39, 44). TRAF3 and TBK1 are further regulated by degradative K48-linked and nondegradative K63-linked ubiquitination, and deubiquitinating TRAF3 inhibits IRF3/7-directed IFN-␤ induction (36,45,46).…”

The Linear Ubiquitin Assembly Complex Modulates Latent Membrane Protein 1 Activation of NF-κB and Interferon Regulatory Factor 7

“…Thus, our findings suggest a potential role for LUBAC in modulation of IRF7-mediated IFN response in innate immunity. In fact, in addition to NF-B activation downstream of pathogen-associated recognition receptors, LUBAC negatively regulates RIG-I-mediated innate immune responses by targeting RIG-I, TRIM25, and IRF3 for degradation (60,61) and by disrupting the TRAF3-MAVS complex (62). LUBAC also promotes IRF3 linear ubiquitination at two specific sites to activate the RLR-induced IRF-3-mediated pathway of apoptosis (63).…”

Regulation of RNF144A E3 Ubiquitin Ligase Activity by Self-association through Its Transmembrane Domain

“…In addition, other RBR E3 ligases have different additional domains on their long N termini and may be responsible for other functions or autoinhibition (2,3). There is no conserved motif in the N termini of RNF144A (a.a. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] and RNF144B (a.a. 1-29). Therefore, there may not be common functions for the N termini of the RNF144 subfamily, such as autoinhibition, which has been seen in other RBR E3 ligases.…”

“…Among hundreds of ubiquitin E3 ligases, the RING1-IBR-RING2 4 (RBR) ubiquitin ligases, which comprise at least 12 complex enzymes, have recently gained attention (2)(3)(4)(5). Most, if not all, of them are involved in the pathogenesis of diseases and embryonic development (5)(6)(7)(8)(9)(10). For example, dysfunction of the RBR ubiquitin ligase Parkin may cause familial autosomal-recessive juvenile Parkinson disease and sporadic early-onset Parkinson disease (11)(12)(13).…”