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. 2020 Jan 7;21(1):e47528.
doi: 10.15252/embr.201847528. Epub 2019 Dec 4.

TRIM21-mediated proteasomal degradation of SAMHD1 regulates its antiviral activity

Zhaolong Li  1 , Chen Huan  1 , Hong Wang  1 , Yue Liu  1 , Xin Liu  1 , Xing Su  1 , Jinghua Yu  1 , Zhilei Zhao  1 , Xiao-Fang Yu  1   2 , Baisong Zheng  1 , Wenyan Zhang  1
Affiliations

TRIM21-mediated proteasomal degradation of SAMHD1 regulates its antiviral activity

Zhaolong Li et al. EMBO Rep. .

Abstract

SAMHD1 possesses multiple functions, but whether cellular factors regulate SAMHD1 expression or its function remains not well characterized. Here, by investigating why cultured RD and HEK293T cells show different sensitivity to enterovirus 71 (EV71) infection, we demonstrate that SAMHD1 is a restriction factor for EV71. Importantly, we identify TRIM21, an E3 ubiquitin ligase, as a key regulator of SAMHD1, which specifically interacts and degrades SAMHD1 through the proteasomal pathway. However, TRIM21 has no effect on EV71 replication itself. Moreover, we prove that interferon production stimulated by EV71 infection induces increased TRIM21 and SAMHD1 expression, whereas increasing TRIM21 overrides SAMHD1 inhibition of EV71 in cells and in a neonatal mouse model. TRIM21-mediated degradation of SAMHD1 also affects SAMHD1-dependent restriction of HIV-1 and the regulation of interferon production. We further identify the functional domains in TRIM21 required for SAMHD1 binding and the ubiquitination site K622 in SAMHD1 and show that phosphorylation of SAMHD1 at T592 also blocks EV71 restriction. Our findings illuminate how EV71 overcomes SAMHD1 inhibition via the upregulation of TRIM21.

Keywords: EV71 infection; SAMHD1 inhibition; interferon induction; regulation; ubiquitin-proteasome degradation.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1. SAMHD1 suppresses EV71 replication
  1. A–D

    The expression of SAMHD1 is negatively correlated with EV71 viral replication ability. HEK293T and RD cells were infected with EV71 at a MOI of 0.1; then, the cells and supernatants were harvested at the indicated time points. (A) Immunoblotting (IB) analysis of EV71 VP1 in cells, with tubulin as a loading control. EV71‐VP1 protein in the supernatants was detected after ultracentrifugation. (B) EV71 viral RNA levels in cell lysates and supernatants were detected by RT–qPCR with GAPDH as a control. (n = 3, mean ± SD, ns stands for no significance, paired t‐test) (C) The mRNA levels of the host restriction factors were detected by RT–qPCR in infected or uninfected HEK293T or RD cells, and the expression levels of the target genes were normalized to GAPDH. (n = 3, mean ± SD, ns stands for no significance, paired t‐test). (D) IB analysis of SAMHD1 and BST‐2 protein levels with tubulin as a loading control. The densities of bands were analyzed with ImageJ software to calculate the values relative to that of tubulin.

  2. E–J

    SAMHD1 knockdown enhances EV71 replication. The stable cell lines pLKO.1 and sh‐SAMHD1 constructed in HEK293T (E) and RD (H) cells were infected with EV71 at a MOI of 0.1 and 0.05, respectively, and cells and supernatants were harvested at the indicated time points. IB analysis of EV71 VP1 and SAMHD1 in cells was performed with tubulin as a loading control. EV71‐VP1 protein in the supernatants was detected after ultracentrifugation. (F and I) EV71 viral RNA in cell lysates was detected by RT–qPCR with GAPDH as a control (n = 3, mean ± SD, *P < 0.05, **P < 0.01, paired t‐test). (G and J) Viral titers in the supernatants were measured by the cytopathic effect method. The results represent the means ± SD from three independent experiments. Statistical significance was analyzed using Student's t‐test (*P < 0.05, **P < 0.01).

  3. K

    HEK293T cells transfected with VR1012, which is a eukaryotic expression vector, or Vpx‐HA were infected with EV71 at a MOI of 0.1, and then, cells and supernatants were harvested at the indicated time points. IB analysis of EV71‐VP1, SAMHD1, and Vpx‐HA in cell lysates was performed with tubulin as a loading control. EV71‐VP1 was detected in the supernatants after ultracentrifugation.

  4. L

    EV71 viral RNA was detected in cell lysates by RT–qPCR with GAPDH as a control (n = 3, mean ± SD, **P < 0.01, paired t‐test).

  5. M

    Viral titers in the supernatants were measured by the cytopathic effect method. The results represent the means ± SD from three independent experiments. Statistical significance was analyzed using Student's t‐test (**P < 0.01).

Source data are available online for this figure.
Figure 2
Figure 2. SAMHD1 is degraded by TRIM21 via the proteasomal pathway
  1. A

    Stable SAMHD1‐HA‐overexpressing cell lines were constructed in HEK293T and RD cells and detected by IB with pLVX as a negative control.

  2. B

    RD SAMHD1‐HA cell lines were treated with dimethyl sulfoxide (DMSO) or 10 μM MG132 for 12 h prior to harvest and subjected to IB with tubulin as a loading control.

  3. C

    RD SAMHD1‐HA cell lines were treated as in (B), and then, HA immunoprecipitation (IP) and IB were performed. The IP elution was analyzed by mass spectrometry.

  4. D, E

    TRIM21 (D) but not TRIM25 (E) induced the degradation of SAMHD1, and MG132 rescued the TRIM21‐mediated degradation of SAMHD1. HEK293T cells were cotransfected with SAMHD1 and VR1012 or TRIM21 or TRIM25 expression plasmids with or without MG132 treatment for 12 h prior to harvest and then subjected to IB with tubulin as a loading control.

  5. F

    Reverse co‐IP confirmed the interaction between SAMHD1 and TRIM21. SAMHD1‐flag was transfected with TRIM21‐HA into HEK293T cells, and then, the cells were treated as in (B) and subjected to HA IP and IB.

  6. G

    Endogenous TRIM21 but not TRIM25 still interacted with SAMHD1. RD‐SAMHD1‐HA cells treated as in (B) were subjected to TRIM21 or TRIM25 IP and IB.

  7. H, I

    (H) mRNA (n = 3, mean ± SD, ***P < 0.001, paired t‐test) and (I) protein levels of TRIM21 in RD and HEK293T cells.

  8. J, K

    TRIM21 (J) but not TRIM25 (K) colocalized with SAMHD1. Images were taken under a Zeiss LZM710 confocal microscope, Bars, 10 μm.

Source data are available online for this figure.
Figure EV1
Figure EV1. TRIM21 knockdown releases SAMHD1 restriction on EV71 replication

  1. IB analysis of RD cells treated with scrambled shRNA or with TRIM21‐specific shRNA with tubulin as a loading control.

  2. RD‐pLKO.1 or RD‐shTRIM21‐3 cells were infected with EV71 at a MOI of 0.05 for the indicated time and harvested for SAMHD1, TRIM21, and EV71‐VP1 detection by IB. Tubulin served as a loading control.

  3. EV71 RNA levels in (B) were detected by RT–qPCR with GAPDH as a control (n = 3, mean ± SD, **P < 0.01, paired t‐test).

  4. PBMCs were isolated from three healthy donors and infected with EV71 at 0.1 MOI. After 72 h, PBMCs were harvested and subjected to IB for SAMHD1, TRIM21, and EV71‐VP1 detection with tubulin as a control.

  5. Viral mRNA level of EV71 was detected in PBMCs by RT–qPCR with GAPDH as a control (n = 3, mean ± SD).

Source data are available online for this figure.
Figure 3
Figure 3. The degradation of SAMHD1 mediated by TRIM21 affects anti‐EV71 restriction of SAMHD1
  1. A–D

    TRIM21 knockout in RD cells released SAMHD1 inhibition on EV71 replication. (A) Illustration of gRNA‐guided TRIM21 knockout in cells. (B) Negative control or RD‐CRISPR‐Cas9‐TRIM21 RD cells were infected with EV71 at a MOI of 0.05 for the indicated time and harvested for SAMHD1, TRIM21, and EV71‐VP1 detection by IB. Tubulin served as a loading control. (C) EV71 RNA levels in (B) were detected by RT–qPCR with GAPDH as a control (n = 3, mean ± SD, **P < 0.01, paired t‐test). (D) Viral titers in the supernatant were measured by the cytopathic effect method. The results represent the means ± SD from three independent experiments. Statistical significance was analyzed using Student's t‐test (**P < 0.01).

  2. E, F

    Overexpression of TRIM21 in HEK293T cells increased EV71 replication by degrading SAMHD1. HEK293T cells were transfected with VR1012 or TRIM21‐HA for 24 h and then infected with EV71 at a MOI of 0.05. (E) Cells were harvested at the indicated time points and subjected to IB with tubulin as a loading control. (F) EV71 viral RNA in cell lysates was detected by RT–qPCR with GAPDH as a control (n = 3, mean ± SD, **P < 0.01, paired t‐test).

  3. G, H

    TRIM21 itself has no effect on EV71 replication. VR1012 or TRIM21 was transfected into pLKO.1 or sh‐SAMHD1 HEK293T cells for 24 h and infected with EV71. (G) Cells were harvested and subjected to IB analysis. (H) Viral titers in the supernatants were measured by the cytopathic effect method. The results represent the means ± SD from three independent experiments. Statistical significance was analyzed using Student's t‐test (*P < 0.05).

Source data are available online for this figure.
Figure EV2
Figure EV2. TRIM21 regulates EV71 replication in SAMHD1‐dependent manner
  1. A, B

    Stable cell lines scrambled gRNA or TRIM21 gRNA constructed in RD cells were transfected with siRNA‐NC or siRNA‐SAMHD1, and then infected with EV71 at 0.1 MOI. After 48 h, cells and supernatants were harvested and analysis by IB (A) and titer detection (B) Viral titers in the supernatants were measured by the cytopathic effect method. The results represent the means ± SD from three independent experiments. Statistical significance was analyzed using Student's t‐test (*P < 0.05, **P < 0.01).

  2. C

    Stable cell lines scrambled gRNA or TRIM21 gRNA constructed in RD cells were treated with 100 μg/ml cycloheximide (CHX) and DMSO or 10 μM MG132. Cells were harvested at the indicated time points and then analyzed by IB. The densities of bands were analyzed with ImageJ software to calculate the values relative to that for tubulin.

  3. D, E

    Stable cell lines pLKO.1 or sh‐SAMHD1 constructed in HEK293T cells were infected with RSV at a MOI of 0.1, and then, the cells were harvested at the indicated time points. IB analysis of RSV proteins and SAMHD1 was performed with tubulin as a loading control. (F) SAMHD1 inhibits VSV within 24 h. VR1012 or TRIM21 was transfected into pLKO.1 or sh‐SAMHD1 HEK293T cells for 24 h and then infected with VSV‐GFP at 0.01 MOI. At the indicated time points, the infectivity of VSV was measured by enumerating GFP‐positive cells. (n = 3, mean ± SD, *P < 0.05, **P < 0.01, paired t‐test).

Source data are available online for this figure.
Figure EV3
Figure EV3. EV71 upregulates TRIM21 by IFN pathway
  1. A, B

    mRNA level of IFN‐α and IFN‐β as well as SAMHD1 and TRIM21 was upregulated upon EV71 infection. HEK293T and RD cells were infected with EV71 at 0.05 MOI and harvested at different time, and then, mRNA level of IFN‐α, IFN‐β (A), TRIM21, and SAMHD1 (B) was detected by RT–qPCR with GAPDH as a control (n = 3, mean ± SD).

  2. C

    TRIM21 is IFN‐induced protein. THP1‐pLKO.1 or THP1‐shTRIM21 cells were stimulated with IFN‐α (100 U/ml) for 24 h, and then, SAMHD1 and TRIM21 were detected by Western blot with tubulin as a control.

  3. D, E

    Upregulation of TRIM21 by EV71 infection is IFNAR1‐dependent. (D) IFNAR knockdown was confirmed by RT–qPCR detection (n = 3, mean ± SD, ***P < 0.001, paired t‐test). (E) RD‐pLKO.1 and RD‐shIFNAR cells were transfected with SAMHD1 siRNA as indicated, then infected with EV71 at 0.05 MOI, and harvested for SAMHD1, TRIM21, and EV71‐VP1 detection 72 h post‐infection by IB with tubulin as a control.

  4. F

    EV71 nonstructural proteins have no effect on SAMHD1 expression. HEK293T cells were transfected with SAMHD1 plus VR1012 or the indicated EV71 nonstructural proteins for 48 h and subjected to IB analysis with tubulin as a loading control; the blots of EV71 nonstructural proteins were asterisked.

Source data are available online for this figure.
Figure 4
Figure 4. The tissue tropism upon EV71 infection in neonatal mouse model is positively correlated with TRIM21 and negatively correlated with SAMHD1
  1. A

    The mRNA levels of SAMHD1 and TRIM21 in different tissues of neonatal mice were detected by RT–qPCR with GAPDH as a control, and the expression of SAMHD1 and TRIM21 in the heart was set as 100% (n = 3, mean ± SD, *P < 0.05, paired t‐test).

  2. B

    The protein levels of SAMHD1 and TRIM21 in different tissues of mice were examined by near‐infrared spectrum (NIR) Western blot with tubulin as a control.

  3. C

    Immunohistochemical (IHC) staining results of SAMHD1 in various tissues of mice. Bars, 100 μm.

  4. D–F

    The mRNA levels of EV71 virus and host factors in mock‐ or EV71‐infected mice were detected by RT–qPCR with GAPDH as a control. The expression of EV71 (D), IFN‐α and IFN‐β (E), and SAMHD1 and TRIM21 (F) were presented, and the levels of corresponding gene in mock‐infected mice were set as 100% (n = 3, mean ± SD, **P < 0.01, paired t‐test).

Source data are available online for this figure.
Figure 5
Figure 5. The degradation of SAMHD1 by TRIM21 affects the anti‐HIV‐1 activity of SAMHD1
  1. A–I

    (A) IB analysis of THP‐1 cells treated with scrambled shRNA, TRIM21‐specific shRNA, or SAMHD1‐specific shRNA. Tubulin served as loading control. (B, E, H) Quantification of SAMHD1 and TRIM21 levels in whole cells in which the indicated genes were knocked down by shRNA. Data are normalized to tubulin and expressed as the fold change over cells treated with pLKO.1 without HIV infection (n = 3, mean ± SD). (C) sh‐SAMHD1 and sh‐TRIM21 THP‐1 cells were treated with PMA for 24 h and infected with the VSV‐G pseudotyped reporter HIV‐1, and then detected 48 h later by flow cytometry analysis (n = 3, mean ± SD, *P < 0.05, **P < 0.01, ***P < 0.001, paired t‐test). (D) IB analysis of MDM cells from three donors transfected with TRIM21 siRNA twice at days 1 and 3, respectively, after MDM differentiation. (F) MDM cells treated with TRIM21 siRNA were infected with VSV‐G‐pseudotyped HIV‐1 reporter and then detected 48 h later by flow cytometry analysis (n = 3, mean ± SD, **P < 0.01, paired t‐test). (G) IB analysis of Jurkat and KG‐1 cells treated with scrambled shRNA or TRIM21‐specific shRNA. (I) Jurkat and KG‐1 cells treated with TRIM21 shRNA were infected with HIV‐1 and then detected 48 h later by flow cytometry analysis (n = 3, mean ± SD, ns stands for no significance, paired t‐test).

Source data are available online for this figure.
Figure EV4
Figure EV4. TRIM21 regulates SAMHD1 function in innate immunity
  1. A–C

    TRIM21 enhanced the expression of IFN‐α and IFN‐β. TRIM21 was transfected into HEK293T cells for 48 h and then treated with hydroxyurea (HU) for the indicated time points. (A) IB analysis of SAMHD1. mRNA levels of IFN‐α (B) and IFN‐β (C) after treatment with HU (n = 3, mean ± SD, *P < 0.05, **P < 0.01, paired t‐test).

  2. D–F

    Increasing SAMHD1 reduced the TRIM21‐induced increase in of IFN‐α and IFN‐β mRNA. HEK293T cells were cotransfected with TRIM21 WT or C16A mutant and increasing doses of SAMHD1 for 48 h and then treated with HU for 4 h. Cells were subjected to IB analysis (D), and the levels of IFN‐α (E) and IFN‐β (F) mRNA were detected by RT–qPCR with GAPDH as a control (n = 3, mean ± SD).

  3. G–I

    TRIM21 enhanced IFN‐α and IFN‐β production in a SAMHD1‐dependent manner. TRIM21 was transfected into pLKO.1 or sh‐SAMHD1 HEK293T cells for 48 h, and then, the cells were treated with HU for 4 h. Cells were subjected to IB analysis (G), and the levels of IFN‐α (H) and IFN‐β (I) mRNA were detected by RT–qPCR with GAPDH as a control (n = 3, mean ± SD, **P < 0.01, paired t‐test).

Source data are available online for this figure.
Figure 6
Figure 6. The interaction between TRIM21 and SAMHD1
  1. A–C

    TRIM21 interacts with SAMHD1 via PRY and SPRY domains. (A) Sketch map of TRIM21 WT and mutants. (B) The effect of TRIM21 on the degradation of SAMHD1. SAMHD1‐flag was cotransfected with VR1012, TRIM21 WT, or the indicated mutant into HEK293T cells for 48 h, and the cells were subjected to IB with tubulin as loading control. (C) SAMHD1‐flag was cotransfected with VR1012 or TRIM21 WT or the indicated mutant for 24 h, and the cells were then treated with 10 μM MG132 for 12 h before harvest and subjected to HA IP and IB.

  2. D

    Map of SAMHD1 WT and truncation mutants.

  3. E

    The effect of TRIM21 on SAMHD1 WT or its mutants. SAMHD1‐HA or the indicated mutant were cotransfected with VR1012 or TRIM21‐flag into HEK293T cells for 48 h, and the cells were subjected to IB with tubulin as a loading control.

  4. F

    SAMHD1‐flag 1–547 was cotransfected with VR1012 or TRIM21‐HA for 24 h, and the cells were then treated with 10 μM MG132 for 12 h before harvest and subjected to HA IP and IB.

  5. G

    SAMHD1 109–626 followed with a His tag or TRIM21‐PRYSPRY followed with a GST tag was expressed in Rosetta (DE3), and pull‐down assay was performed with Ni Sepharose (up) and GST Sepharose (down), respectively.

  6. H

    FRET analysis indicates interaction between YFP‐SAMHD1 and CFP‐TRIM21. A representative image of SAMHD1‐YFP (yellow) and ECFP‐TRIM21 (cyan)‐expressing cells before and after photobleaching the acceptor fluorophore, YFP. The region chosen for photobleaching is marked (white open box), Bars, 10 μm. The quantization of fluorescence brightness was analyzed by ImageJ (n = 3, mean ± SD, ns stands for no significance, *P < 0.05, paired t‐test).

  7. I

    The microscale thermophoresis curve for the interaction between SAMHD1 and TRIM21. Alexa Fluor® 647‐labeled SAMHD1 at a concentration of 20 nM was incubated with twofold dilution series of unlabeled TRIM21 (3 μM to 9.16E‐05 μM). The curve represents the signal recorded from three measurements. The normalized fluorescence thermophoretic signals were plotted against the concentration of TRIM21 with mean values ± standard deviation as well as a fitting to a 1:1 binding model (NanoTemper® Analysis software, F Norm = FHot/FCold). The K d of this interaction was determined to be 270 ± 92 nM. The data were a representative of three independent experiments using different dilution.

Source data are available online for this figure.
Figure 7
Figure 7. Binding sites and ubiquitination sites in SAMHD1 required for TRIM21 recognition

  1. The effect of TRIM21 on SAMHD1 proteins from various species. HEK293T cells were transfected with VR1012 or TRIM21 and the indicated SAMHD1 expression vector and then subjected to IB analysis.

  2. Identification of amino acids presented only in SAMHD1 of Canis and Gallus but not in other SAMHD1 proteins.

  3. Construction of hSAMHD1 mutants with amino acid alterations.

  4. The effect of TRIM21 on hSAMHD1 mutants. HEK293T cells were transfected with VR1012 or TRIM21 and SAMHD1 mutants for 48 h and then subjected to IB analysis.

  5. SAMHD1‐flag WT or the G153S or G183R mutant was cotransfected with VR1012 or TRIM21‐HA for 24 h, and the cells were then treated with 10 μM MG132 for 12 h before harvest and subjected to HA IP and IB.

  6. Sketch map of potential ubiquitination sites on SAMHD1.

  7. SAMHD1‐HA WT or the indicated mutants were cotransfected with VR1012 or TRIM21‐flag into HEK293T cells for 48 h, and the cells were subjected to IB with tubulin as a loading control.

  8. SAMHD1‐HA WT and VR1012 or TRIM21 were cotransfected with K48‐only and K63‐only ubiquitin‐flag into HEK293T cells for 24 h, and the cells were then treated with 10 μM MG132 for 12 h before harvest and subjected to HA IP and IB with tubulin as a loading control.

  9. K48‐only ubiquitin‐flag and SAMHD1‐HA WT or mutant K622R were cotransfected with VR1012 or TRIM21 into HEK293T cells as indicated. The cells were then treated with 10 μM MG132 for 12 h before harvest and subjected to HA IP and IB with tubulin as a loading control.

  10. VR1012, SAMHD1‐HA WT, or the K622R mutant was transfected into HEK293T‐shSAMHD1 cells for 24 h. The cells were then infected with EV71 at a MOI of 0.1 and harvested at the indicated time points. SAMHD1‐HA, TRIM21, and EV71‐VP1 were detected by IB with tubulin as a loading control.

Data information: (A, D–E) Tubulin served as a loading control.Source data are available online for this figure.
Figure EV5
Figure EV5. Phosphorylated SAMHD1 loses the ability to inhibit EV71 replication
  1. A

    Stable sh‐SAMHD1 HEK293T cells were transfected with VR1012, SAMHD1 WT, or the indicated mutant for 24 h and then infected with EV71 at a MOI of 0.05 for 72 h. Cells were harvested and subjected to IB analysis.

  2. B

    IB analysis of T592‐phosphorylated SAMHD1 and total SAMHD1 in RD and HEK293T cells.

  3. C

    The effect of TRIM21 on endogenous phosphorylated SAMHD1 and total SAMHD1.

  4. D

    The effect of TRIM21 on ectopic phosphorylated and unphosphorylated SAMHD1.

  5. E, F

    TRIM21 directly induced the degradation of SAMHD1 but not via changing cell cycle or upregulating cyclin L2 expression. (E) TRIM21 has no effect on the G0–G1 transition in MDM. (F) TRIM21 has no effect on the expression of cyclin L2 in MDM.

Data information: (A–F) Tubulin served as a loading control.Source data are available online for this figure.
Figure 8
Figure 8. Proposed mechanism of TRIM21‐mediated degradation of SAMHD1
Host restriction factor SAMHD1 but not phosphorylated SAMHD1 restricts EV71 replication. However, EV71 infection overcomes the inhibitory of SAMHD1 by upregulating TRIM21, an E3 ubiquitin ligase, which induces the degradation of SAMHD1 via proteasome pathway. Moreover, the degradation of SAMHD1 induced by TRIM21 also affects its functions on HIV restriction and IFN production.
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