PCBP2 mediates degradation of the adaptor MAVS via the HECT ubiquitin ligase AIP4.
MAVS is critical in innate antiviral immunity as the sole adaptor for RIG-I-like helicases. MAVS regulation is essential for the prevention of excessive harmful immune responses. Here we identify PCBP2 as a negative regulator in MAVS-mediated signaling. Overexpression of PCBP2 abrogated cellular responses to viral infection, whereas knockdown of PCBP2 exerted the opposite effect. PCBP2 was induced after viral infection, and its interaction with MAVS led to proteasomal degradation of MAVS. PCBP2 recruited the HECT domain-containing E3 ligase AIP4 to polyubiquitinate and degrade MAVS. MAVS was degraded after viral infection in wild-type mouse embryonic fibroblasts but remained stable in AIP4-deficient (Itch(-/-)) mouse embryonic fibroblasts, coupled with greatly exaggerated and prolonged antiviral responses. The PCBP2-AIP4 axis defines a new signaling cascade for MAVS degradation and 'fine tuning' of antiviral innate immunity.
You
Fuping
F
The Education Ministry Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China.
Sun
Hui
H
Zhou
Xiang
X
Sun
Wenxiang
W
Liang
Shimin
S
Zhai
Zhonghe
Z
Jiang
Zhengfan
Z
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D006801:Humans; D007113:Immunity, Innate; D051379:Mice; D018345:Mice, Knockout; D009522:Newcastle disease virus / Q000276:immunology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D029082:Sendai virus / Q000276:immunology; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018116:Vesiculovirus / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D044767:Ubiquitin-Protein Ligases; C512612:MAVS protein, mouse; C505371:MAVS protein, human; C501903:PCBP2 protein, human; C501904:Pcbp2 protein, mouse; C432966:ITCH protein, human; C471637:Itch protein, mouse