Wang Y, Tong X, Omoregie ES, Liu W, Meng S, Ye X

The recognition between RIG-I-like receptors (RLRs) and viral RNA triggers an intracellular cascade of signaling to induce the expression of type I interferons (IFNs). Both positive and negative regulation on RLRs signaling pathway are important for host anti-viral immune response. Here we demonstrated that tetraspanin protein TSPAN6 inhibits RLR signaling ...

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by affecting the formation of adaptor MAVS (mitochondria antiviral signaling) centered signalosome. We found that overexpression of TSPAN6 impairs RLR mediated activation of ISRE, NF-kappaB and IFN-beta promoters while knockdown of TSPAN6 enhances RLR mediated signaling pathway. Interestingly, as RLR pathway is activated, TSPAN6 undergoes the K-63-linked ubiquitination which promotes its association with MAVS. The interaction of TSPAN6 and MAVS interferes 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. On the whole, we concluded that TSPAN6 functions as a negative regulator in RLR pathway by interacting with MAVS in a ubiquitination dependent manner.

Date: Aug. 20, 2012

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