TY - JOUR
T1 - A Viral Protein Restricts Drosophila RNAi Immunity by Regulating Argonaute Activity and Stability
AU - Nayak, Arabinda
AU - Kim, Dong Young
AU - Trnka, Michael J.
AU - Kerr, Craig H.
AU - Lidsky, Peter V.
AU - Stanley, David J.
AU - Rivera, Brianna Monique
AU - Li, Kathy H.
AU - Burlingame, Alma L.
AU - Jan, Eric
AU - Frydman, Judith
AU - Gross, John D.
AU - Andino, Raul
N1 - Publication details (e.g. title, author(s), publication statuses and dates) are captured on an “AS IS” and “AS AVAILABLE” basis at the time of record harvesting from the data source. Suggestions for further amendments or supplementary information can be sent to [email protected].
PY - 2018/10/10
Y1 - 2018/10/10
N2 - The dicistrovirus, Cricket paralysis virus (CrPV) encodes an RNA interference (RNAi) suppressor, 1A, which modulates viral virulence. Using the Drosophila model, we combined structural, biochemical, and virological approaches to elucidate the strategies by which CrPV-1A restricts RNAi immunity. The atomic resolution structure of CrPV-1A uncovered a flexible loop that interacts with Argonaute 2 (Ago-2), thereby inhibiting Ago-2 endonuclease-dependent immunity. Mutations disrupting Ago-2 binding attenuates viral pathogenesis in wild-type but not Ago-2-deficient flies. CrPV-1A also contains a BC-box motif that enables the virus to hijack a host Cul2-Rbx1-EloBC ubiquitin ligase complex, which promotes Ago-2 degradation and virus replication. Our study uncovers a viral-based dual regulatory program that restricts antiviral immunity by direct interaction with and modulation of host proteins. While the direct inhibition of Ago-2 activity provides an efficient mechanism to establish infection, the recruitment of a ubiquitin ligase complex enables CrPV-1A to amplify Ago-2 inactivation to restrict further antiviral RNAi immunity. Viruses suppress, and thereby evade, RNAi-mediated immunity via several distinct mechanisms, which are not well understood. In a Drosophila infection model, Nayak et al. reveal that the viral RNAi suppressor protein CrPV-1A utilizes a dual regulatory mechanism to evade RNAi-mediated immunity: direct enzymatic inhibition and E3-ligase-mediated degradation of Ago-2. © 2018
AB - The dicistrovirus, Cricket paralysis virus (CrPV) encodes an RNA interference (RNAi) suppressor, 1A, which modulates viral virulence. Using the Drosophila model, we combined structural, biochemical, and virological approaches to elucidate the strategies by which CrPV-1A restricts RNAi immunity. The atomic resolution structure of CrPV-1A uncovered a flexible loop that interacts with Argonaute 2 (Ago-2), thereby inhibiting Ago-2 endonuclease-dependent immunity. Mutations disrupting Ago-2 binding attenuates viral pathogenesis in wild-type but not Ago-2-deficient flies. CrPV-1A also contains a BC-box motif that enables the virus to hijack a host Cul2-Rbx1-EloBC ubiquitin ligase complex, which promotes Ago-2 degradation and virus replication. Our study uncovers a viral-based dual regulatory program that restricts antiviral immunity by direct interaction with and modulation of host proteins. While the direct inhibition of Ago-2 activity provides an efficient mechanism to establish infection, the recruitment of a ubiquitin ligase complex enables CrPV-1A to amplify Ago-2 inactivation to restrict further antiviral RNAi immunity. Viruses suppress, and thereby evade, RNAi-mediated immunity via several distinct mechanisms, which are not well understood. In a Drosophila infection model, Nayak et al. reveal that the viral RNAi suppressor protein CrPV-1A utilizes a dual regulatory mechanism to evade RNAi-mediated immunity: direct enzymatic inhibition and E3-ligase-mediated degradation of Ago-2. © 2018
KW - Ago-2
KW - Ago-2 degradation
KW - antiviral immunity
KW - CrPV
KW - E3 ligase
KW - insects
KW - RNAi
KW - RNAi suppressor
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U2 - 10.1016/j.chom.2018.09.006
DO - 10.1016/j.chom.2018.09.006
M3 - RGC 21 - Publication in refereed journal
C2 - 30308158
SN - 1931-3128
VL - 24
SP - 542-557.e9
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 4
ER -