PMID- 35533808
OWN - NLM
STAT- MEDLINE
DCOM- 20220829
LR  - 20220910
IS  - 1995-820X (Electronic)
IS  - 1674-0769 (Print)
IS  - 1995-820X (Linking)
VI  - 37
IP  - 4
DP  - 2022 Aug
TI  - STUB1 regulates antiviral RNAi through inducing ubiquitination and degradation of 
      Dicer and AGO2 in mammals.
PG  - 569-580
LID - S1995-820X(22)00080-3 [pii]
LID - 10.1016/j.virs.2022.05.001 [doi]
AB  - RNA interference (RNAi) is an intrinsic antiviral immune mechanism conserved in 
      diverse eukaryotic organisms. However, the mechanism by which antiviral RNAi in 
      mammals is regulated is poorly understood. In this study, we uncovered that the 
      E3 ubiquitin ligase STIP1 homology and U-box-containing protein 1 (STUB1) was a 
      new regulator of the RNAi machinery in mammals. We found that STUB1 interacted 
      with and ubiquitinated AGO2, and targeted it for degradation in a 
      chaperon-dependent manner. STUB1 promoted the formation of Lys48 (K48)-linked 
      polyubiquitin chains on AGO2, and facilitated AGO2 degradation through 
      ubiquitin-proteasome system. In addition to AGO2, STUB1 also induced the protein 
      degradation of AGO1, AGO3 and AGO4. Further investigation revealed that STUB1 
      also regulated Dicer's ubiquitination via K48-linked polyubiquitin and induced 
      the degradation of Dicer as well as its specialized form, termed antiviral Dicer 
      (aviDicer) that expresses in mammalian stem cells. Moreover, we found that STUB1 
      deficiency up-regulated Dicer and AGO2, thereby enhancing the RNAi response and 
      efficiently inhibiting viral replication in mammalian cells. Using the newborn 
      mouse model of Enterovirus A71 (EV-A71), we confirmed that STUB1 deficiency 
      enhanced the virus-derived siRNAs production and antiviral RNAi, which elicited a 
      potent antiviral effect against EV-A71 infection in vivo. In summary, our 
      findings uncovered that the E3 ubiquitin ligase STUB1 was a general regulator of 
      the RNAi machinery by targeting Dicer, aviDicer and AGO1-4. Moreover, STUB1 
      regulated the RNAi response through mediating the abundance of Dicer and AGO2 
      during viral infection, thereby providing novel insights into the regulation of 
      antiviral RNAi in mammals.
CI  - Copyright (c) 2022 The Authors. Publishing services by Elsevier B.V. All rights 
      reserved.
FAU - Zhang, Shumin
AU  - Zhang S
AD  - State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of 
      Sciences, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 
      100049, China.
FAU - Zhang, Xuhua
AU  - Zhang X
AD  - State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of 
      Sciences, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 
      100049, China.
FAU - Bie, Yuanyuan
AU  - Bie Y
AD  - State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of 
      Sciences, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 
      100049, China.
FAU - Kong, Jing
AU  - Kong J
AD  - State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of 
      Sciences, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 
      100049, China.
FAU - Wang, An
AU  - Wang A
AD  - State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of 
      Sciences, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 
      100049, China.
FAU - Qiu, Yang
AU  - Qiu Y
AD  - State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of 
      Sciences, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 
      100049, China. Electronic address: yangqiu@wh.iov.cn.
FAU - Zhou, Xi
AU  - Zhou X
AD  - State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of 
      Sciences, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 
      100049, China. Electronic address: zhouxi@wh.iov.cn.
LA  - eng
PT  - Journal Article
DEP - 20220506
PL  - Netherlands
TA  - Virol Sin
JT  - Virologica Sinica
JID - 101514185
RN  - 0 (Ago2 protein, mouse)
RN  - 0 (Antiviral Agents)
RN  - 0 (Argonaute Proteins)
RN  - 0 (Ubiquitin)
RN  - 120904-94-1 (Polyubiquitin)
RN  - EC 2.3.2.27 (Stub1 protein, mouse)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 3.1.26.3 (Dicer1 protein, mouse)
RN  - EC 3.1.26.3 (Ribonuclease III)
RN  - EC 3.6.4.13 (DEAD-box RNA Helicases)
SB  - IM
MH  - Animals
MH  - *Antiviral Agents
MH  - Argonaute Proteins
MH  - DEAD-box RNA Helicases
MH  - Mammals/metabolism
MH  - Mice
MH  - *Polyubiquitin/genetics/metabolism
MH  - RNA Interference
MH  - Ribonuclease III
MH  - Ubiquitin/genetics
MH  - Ubiquitin-Protein Ligases/genetics/metabolism
MH  - Ubiquitination
PMC - PMC9437610
OTO - NOTNLM
OT  - Antiviral RNAi
OT  - Argonaute 2 (AGO2)
OT  - Dicer
OT  - STIP1 homology and U-box-containing protein 1 (STUB1)
EDAT- 2022/05/10 06:00
MHDA- 2022/08/30 06:00
PMCR- 2022/05/06
CRDT- 2022/05/09 19:25
PHST- 2022/03/01 00:00 [received]
PHST- 2022/04/13 00:00 [accepted]
PHST- 2022/05/10 06:00 [pubmed]
PHST- 2022/08/30 06:00 [medline]
PHST- 2022/05/09 19:25 [entrez]
PHST- 2022/05/06 00:00 [pmc-release]
AID - S1995-820X(22)00080-3 [pii]
AID - 10.1016/j.virs.2022.05.001 [doi]
PST - ppublish
SO  - Virol Sin. 2022 Aug;37(4):569-580. doi: 10.1016/j.virs.2022.05.001. Epub 2022 May 
      6.