TY - JOUR
T1 - MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response
AU - Hou, Fajian
AU - Sun, Lijun
AU - Zheng, Hui
AU - Skaug, Brian
AU - Jiang, Qiu Xing
AU - Chen, Zhijian J.
N1 - Funding Information:
We thank Xiaomo Jiang for the MDA5 plasmids. This work was supported by grants from NIH (RO1-GM63692) and the Welch Foundation (I-1389). H.Z. was supported by a Welch Foundation grant (I-1684) and partially by a EUREKA grant from NIH (R01-GM88745 to Q.-X.J.). B.S is supported by an NIH predoctoral training grant (GM007062). Z.J.C. is an Investigator of Howard Hughes Medical Institute.
PY - 2011/8/5
Y1 - 2011/8/5
N2 - In response to viral infection, RIG-I-like RNA helicases bind to viral RNA and activate the mitochondrial protein MAVS, which in turn activates the transcription factors IRF3 and NF-κB to induce type I interferons. We have previously shown that RIG-I binds to unanchored lysine-63 (K63) polyubiquitin chains and that this binding is important for MAVS activation; however, the mechanism underlying MAVS activation is not understood. Here, we show that viral infection induces the formation of very large MAVS aggregates, which potently activate IRF3 in the cytosol. We find that a fraction of recombinant MAVS protein forms fibrils that are capable of activating IRF3. Remarkably, the MAVS fibrils behave like prions and effectively convert endogenous MAVS into functional aggregates. We also show that, in the presence of K63 ubiquitin chains, RIG-I catalyzes the conversion of MAVS on the mitochondrial membrane to prion-like aggregates. These results suggest that a prion-like conformational switch of MAVS activates and propagates the antiviral signaling cascade.
AB - In response to viral infection, RIG-I-like RNA helicases bind to viral RNA and activate the mitochondrial protein MAVS, which in turn activates the transcription factors IRF3 and NF-κB to induce type I interferons. We have previously shown that RIG-I binds to unanchored lysine-63 (K63) polyubiquitin chains and that this binding is important for MAVS activation; however, the mechanism underlying MAVS activation is not understood. Here, we show that viral infection induces the formation of very large MAVS aggregates, which potently activate IRF3 in the cytosol. We find that a fraction of recombinant MAVS protein forms fibrils that are capable of activating IRF3. Remarkably, the MAVS fibrils behave like prions and effectively convert endogenous MAVS into functional aggregates. We also show that, in the presence of K63 ubiquitin chains, RIG-I catalyzes the conversion of MAVS on the mitochondrial membrane to prion-like aggregates. These results suggest that a prion-like conformational switch of MAVS activates and propagates the antiviral signaling cascade.
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U2 - 10.1016/j.cell.2011.06.041
DO - 10.1016/j.cell.2011.06.041
M3 - Article
C2 - 21782231
AN - SCOPUS:79961133270
SN - 0092-8674
VL - 146
SP - 448
EP - 461
JO - Cell
JF - Cell
IS - 3
ER -