Tetraspanin 6 (TSPAN6) negatively regulates retinoic acid-inducible gene I-like receptor-mediated immune signaling in a ubiquitination-dependent manner.
The recognition between retinoic acid-inducible gene I-like receptors (RLRs) and viral RNA triggers an intracellular cascade of signaling to induce the expression of type I IFNs. Both positive and negative regulation of the RLR signaling pathway are important for the host antiviral immune response. Here, we demonstrate that the tetraspanin protein TSPAN6 inhibits RLR signaling by affecting the formation of the adaptor MAVS (mitochondrial antiviral signaling)-centered signalosome. We found that overexpression of TSPAN6 impaired RLR-mediated activation of IFN-stimulated response element, NF-κB, and IFN-β promoters, whereas knockdown of TSPAN6 enhanced the RLR-mediated signaling pathway. Interestingly, as the RLR pathway was activated, TSPAN6 underwent Lys-63-linked ubiquitination, which promoted its association with MAVS. The interaction of TSPAN6 and MAVS interfered with the recruitment of RLR downstream molecules TRAF3, MITA, and IRF3 to MAVS. Further study revealed that the first transmembrane domain of TSPAN6 is critical for its ubiquitination and association with MAVS as well as its inhibitory effect on RLR signaling. We concluded that TSPAN6 functions as a negative regulator of the RLR pathway by interacting with MAVS in a ubiquitination-dependent manner.
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
Yetao
Y
Wang
Xiaomei
X
Tong
Ehimwenma Sheena
ES
Omoregie
Wenjun
W
Liu
Songdong
S
Meng
Xin
X
Ye
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism; D000072640:Interferon-Induced Helicase, IFIH1; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic; D015398:Signal Transduction / Q000502:physiology*; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000378:metabolism; D059470:Tetraspanins / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*; D000099197:STING Protein
D048868:Adaptor Proteins, Signal Transducing; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D050838:Interferon Regulatory Factor-3; D000072640:Interferon-Induced Helicase, IFIH1; D008565:Membrane Proteins; D016328:NF-kappa B; D011971:Receptors, Immunologic; D048008:TNF Receptor-Associated Factor 3; D059470:Tetraspanins; C494232:IRF3 protein, human; C505371:MAVS protein, human; C532857:STING1 protein, human; D000099197:STING Protein; C090656:TRAF3 protein, human; C115729:TSPAN6 protein, human; C452820:RIGI protein, human; C452815:IFIH1 protein, human