Linear ubiquitination of NEMO negatively regulates the interferon antiviral response through disruption of the MAVS-TRAF3 complex.
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.
Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Canada.
S Mehdi
SM
Belgnaoui
Suzanne
S
Paz
Sara
S
Samuel
Marie-Line
ML
Goulet
Qiang
Q
Sun
Marjolein
M
Kikkert
Kazuhiro
K
Iwai
Ivan
I
Dikic
John
J
Hiscott
Rongtuan
R
Lin
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007372:Interferons / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D054243:Vesicular Stomatitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D014721:Vesicular stomatitis Indiana virus / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; C491731:IKBKG protein, human; C505371:MAVS protein, human; D048008:TNF Receptor-Associated Factor 3; D007372:Interferons; D051550:I-kappa B Kinase