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 inhibits RLR signaling by affecting the formation of the adaptor MAVS (mitochondrial antiviral signaling)-centered signalosome. We found that overexpression of Tduanyu1842N6 impaired RLR-mediated activation of IFN-stimulated response element, NF-κB, and IFN-β promoters, whereas knockdown of Tduanyu1842N6 enhanced the RLR-mediated signaling pathway. Interestingly, as the RLR pathway was activated, Tduanyu1842N6 underwent Lys-63-linked ubiquitination, which promoted its association with MAVS. The interaction of Tduanyu1842N6 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 Tduanyu1842N6 is critical for its ubiquitination and association with MAVS as well as its inhibitory effect on RLR signaling. We concluded that Tduanyu1842N6 functions as a negative regulator of the RLR pathway by interacting with MAVS in a ubiquitination-dependent manner.

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