PMID- 33172327
OWN - NLM
STAT- MEDLINE
DCOM- 20220407
LR  - 20240403
IS  - 1554-8635 (Electronic)
IS  - 1554-8627 (Print)
IS  - 1554-8627 (Linking)
VI  - 17
IP  - 10
DP  - 2021 Oct
TI  - Equine lentivirus counteracts SAMHD1 restriction by Rev-mediated degradation of 
      SAMHD1 via the BECN1-dependent lysosomal pathway.
PG  - 2800-2817
LID - 10.1080/15548627.2020.1846301 [doi]
AB  - The innate immune restriction factor SAMHD1 can inhibit diverse viruses in 
      myeloid cells. Mechanistically, SAMHD1 inhibits lentiviral replication including 
      HIV-1 by depleting the nucleotide pool to interfere with their reverse 
      transcription. Equine infectious anemia virus (EIAV) is an ancient lentivirus 
      that preferentially attacks macrophages. However, the mechanism by which EIAV 
      successfully establishes infection in macrophages with functional SAMHD1 remains 
      unclear. Here, we demonstrate that while equine SAMDH1 can limit EIAV replication 
      in equine macrophages at the reverse transcription stage, the antiviral effect is 
      counteracted by the well-known transcriptional regulator Rev, which downregulates 
      equine SAMHD1 through the lysosomal pathway. Remarkably, Rev hijacks BECN1 
      (beclin 1) and PIK3C3 to mediate SAMHD1 degradation in a canonical 
      macroautophagy/autophagy-independent pathway. Our study illustrates that equine 
      lentiviral Rev possesses important functions in evading cellular innate immunity 
      in addition to its RNA regulatory function, and may provide new insights into the 
      co-evolutionary arms race between SAMHD1 and lentiviruses.Abbreviations:3-MA: 
      3-methyladenine; AA: amino acid; ACTB: actin beta; AD: activation domain; ATG: 
      autophagy related; Baf A1: bafilomycin A(1); BD: binding domain; BECN1: beclin 1; 
      BH3: BCL2-homology-3 domain; BiFC: bimolecular fluorescence complementation; CCD: 
      coiled-coil domain; class III PtdIns3K: class III phosphatidylinositol 3-kinase; 
      CQ: chloroquine; Co-IP: co-immunoprecipitation; dNTPase: dGTP-stimulated 
      deoxynucleoside triphosphate triphosphohydrolase; ECD: evolutionarily conserved 
      domain; EIAV: equine infectious anemia virus; eMDMs: equine monocyte-derived 
      macrophages; GFP: green fluorescent protein; HD: histidine-aspartic; HIV-1: human 
      immunodeficiency virus-1; hpi: hours post infection; hpt: hours post 
      transfection; KO: knockout; LAMP2: lysosomal associated membrane protein 2; LMB: 
      leptomycin B; PMA: phorbol 12-myristate 13-acetate; MAP1LC3/LC3: microtubule 
      associated protein 1 light chain 3; ND: unknown non-essential domain; NES: 
      nuclear export signal; NLS: localization signal; NS: statistically 
      non-significant; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; 
      RBD: RNA binding domain; RT: reverse transcriptase; siRNAs: small interfering 
      RNAs; SAMHD1: SAM and HD domain containing deoxynucleoside triphosphate 
      triphosphohydrolase 1; SIV: simian immunodeficiency virus; VN: C-terminal 
      residues of Venus 174 to 238; VC: N-terminal residues 2 to 173 of Venus.
FAU - Ren, Huiling
AU  - Ren H
AD  - State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research 
      Institute, the Chinese Academy of Agricultural Sciences, Harbin, China.
FAU - Yin, Xin
AU  - Yin X
AUID- ORCID: 0000-0003-2357-6718
AD  - State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research 
      Institute, the Chinese Academy of Agricultural Sciences, Harbin, China.
FAU - Su, Chao
AU  - Su C
AD  - State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research 
      Institute, the Chinese Academy of Agricultural Sciences, Harbin, China.
FAU - Guo, Miaomiao
AU  - Guo M
AUID- ORCID: 0000-0001-7054-9873
AD  - State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research 
      Institute, the Chinese Academy of Agricultural Sciences, Harbin, China.
FAU - Wang, Xue-Feng
AU  - Wang XF
AD  - State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research 
      Institute, the Chinese Academy of Agricultural Sciences, Harbin, China.
FAU - Na, Lei
AU  - Na L
AD  - State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research 
      Institute, the Chinese Academy of Agricultural Sciences, Harbin, China.
FAU - Lin, Yuezhi
AU  - Lin Y
AD  - State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research 
      Institute, the Chinese Academy of Agricultural Sciences, Harbin, China.
FAU - Wang, Xiaojun
AU  - Wang X
AUID- ORCID: 0000-0003-4521-4099
AD  - State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research 
      Institute, the Chinese Academy of Agricultural Sciences, Harbin, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20201124
PL  - United States
TA  - Autophagy
JT  - Autophagy
JID - 101265188
RN  - 0 (Beclin-1)
RN  - EC 3.1.5.- (SAM Domain and HD Domain-Containing Protein 1)
SB  - IM
MH  - Animals
MH  - *Autophagy
MH  - Beclin-1/metabolism
MH  - Horses
MH  - *Lentiviruses, Equine
MH  - Lysosomes/metabolism
MH  - SAM Domain and HD Domain-Containing Protein 1/genetics
PMC - PMC8525956
OTO - NOTNLM
OT  - BECN1
OT  - EIAV
OT  - HIV-1
OT  - PIK3C3
OT  - Rev
OT  - SAMHD1
OT  - innate immunity
OT  - lysosome
OT  - non-canonical autophagy
OT  - retrovirus
COIS- The authors declare no competing interests.
EDAT- 2020/11/12 06:00
MHDA- 2022/04/08 06:00
PMCR- 2020/11/24
CRDT- 2020/11/11 05:34
PHST- 2020/11/12 06:00 [pubmed]
PHST- 2022/04/08 06:00 [medline]
PHST- 2020/11/11 05:34 [entrez]
PHST- 2020/11/24 00:00 [pmc-release]
AID - 1846301 [pii]
AID - 10.1080/15548627.2020.1846301 [doi]
PST - ppublish
SO  - Autophagy. 2021 Oct;17(10):2800-2817. doi: 10.1080/15548627.2020.1846301. Epub 
      2020 Nov 24.