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Novel Role for Protein Inhibitor of Activated STAT 4 (PIAS4) in the Restriction of Herpes Simplex Virus 1 by the Cellular Intrinsic Antiviral Immune Response.

Conn KL, Wasson P, McFarlane S, Tong L, Brown JR, Grant KG, Domingues P, Boutell C - J. Virol. (2016)

Bottom Line: Despite characterization of the host factors that rely on SUMOylation to exert their antiviral effects, the enzymes that mediate these SUMOylation events remain to be defined.Moreover, in the absence of ICP0, high-molecular-weight SUMO-conjugated proteins do not accumulate if HSV-1 DNA does not replicate.The protein inhibitor of activated STAT (PIAS) family of SUMO ligases is predominantly associated with the suppression of innate immune signaling.

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Affiliation: MRC-University of Glasgow Centre for Virus Research (CVR), Glasgow, Scotland, United Kingdom.

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PIAS4 accumulates in HSV-1 replication compartments. (A to D) Confocal images show the nuclear localization of PIAS1 (A), PIAS2 (B), PIAS3 (C), or PIAS4 (D) in HFt cells mock infected (mock) or infected with 0.002 PFU of wild-type HSV-1 or 2 PFU of ICP0- mutant (ΔICP0) HSV-1 per cell for 16 h. Wild-type and mutant HSV-1 strains expressed eYFP-ICP4, the accumulation of which was used to visualize replication compartments within cells at the edge of developing plaques (6). PIAS proteins were visualized by indirect immunofluorescence (red). Insets (dashed boxes in panel D) highlight regions of PIAS4 localization within replication compartments. (E) Confocal images show the nuclear localization of PIAS4 and SUMO2/3 within wild-type or ICP0- mutant HSV-1 replication compartments in cells infected as described above. ICP4 (green), PIAS4 (red), and SUMO2/3 (cyan) were visualized by indirect immunofluorescence. Nuclei were visualized by DAPI (blue).
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Figure 2: PIAS4 accumulates in HSV-1 replication compartments. (A to D) Confocal images show the nuclear localization of PIAS1 (A), PIAS2 (B), PIAS3 (C), or PIAS4 (D) in HFt cells mock infected (mock) or infected with 0.002 PFU of wild-type HSV-1 or 2 PFU of ICP0- mutant (ΔICP0) HSV-1 per cell for 16 h. Wild-type and mutant HSV-1 strains expressed eYFP-ICP4, the accumulation of which was used to visualize replication compartments within cells at the edge of developing plaques (6). PIAS proteins were visualized by indirect immunofluorescence (red). Insets (dashed boxes in panel D) highlight regions of PIAS4 localization within replication compartments. (E) Confocal images show the nuclear localization of PIAS4 and SUMO2/3 within wild-type or ICP0- mutant HSV-1 replication compartments in cells infected as described above. ICP4 (green), PIAS4 (red), and SUMO2/3 (cyan) were visualized by indirect immunofluorescence. Nuclei were visualized by DAPI (blue).

Mentions: To investigate the potential significance of the accumulation of HMW SUMO-conjugated proteins during ICP0- mutant HSV-1 infection, the SUMO E3 ligase(s) that could mediate these SUMOylation events was analyzed, starting with the PIAS protein family. Consistent with other reports, PIAS proteins in HFt cells were predominantly nuclear, with microspeckled distributions characteristic of localization at matrix-associated regions (MARs) (Fig. 2A to D, mock) (65–67). While a subpopulation of PIAS1 localized to PML-NBs, substantial localization of PIAS2, PIAS3, or PIAS4 at these structures was not detected in this cell type (Fig. 2A to D, mock, and data not shown) (38, 66). PIAS4 robustly relocalized to viral replication compartments, whereas PIAS1, PIAS2, and PIAS3 did not (Fig. 2A to D). The relocalization of PIAS4 was independent of ICP0, as it occurred during wild-type or ICP0- mutant HSV-1 infection (Fig. 2D). PIAS4 is thus identified as a SUMO E3 ligase that accumulates in herpesvirus replication compartments. SUMO2/3 also accumulated in HSV-1 replication compartments, although only in the absence of ICP0 (Fig. 2E). Therefore, during ICP0- mutant HSV-1 infection, the majority of nuclear PIAS4 and SUMO2/3 localize in replication compartments.


Novel Role for Protein Inhibitor of Activated STAT 4 (PIAS4) in the Restriction of Herpes Simplex Virus 1 by the Cellular Intrinsic Antiviral Immune Response.

Conn KL, Wasson P, McFarlane S, Tong L, Brown JR, Grant KG, Domingues P, Boutell C - J. Virol. (2016)

PIAS4 accumulates in HSV-1 replication compartments. (A to D) Confocal images show the nuclear localization of PIAS1 (A), PIAS2 (B), PIAS3 (C), or PIAS4 (D) in HFt cells mock infected (mock) or infected with 0.002 PFU of wild-type HSV-1 or 2 PFU of ICP0- mutant (ΔICP0) HSV-1 per cell for 16 h. Wild-type and mutant HSV-1 strains expressed eYFP-ICP4, the accumulation of which was used to visualize replication compartments within cells at the edge of developing plaques (6). PIAS proteins were visualized by indirect immunofluorescence (red). Insets (dashed boxes in panel D) highlight regions of PIAS4 localization within replication compartments. (E) Confocal images show the nuclear localization of PIAS4 and SUMO2/3 within wild-type or ICP0- mutant HSV-1 replication compartments in cells infected as described above. ICP4 (green), PIAS4 (red), and SUMO2/3 (cyan) were visualized by indirect immunofluorescence. Nuclei were visualized by DAPI (blue).
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Figure 2: PIAS4 accumulates in HSV-1 replication compartments. (A to D) Confocal images show the nuclear localization of PIAS1 (A), PIAS2 (B), PIAS3 (C), or PIAS4 (D) in HFt cells mock infected (mock) or infected with 0.002 PFU of wild-type HSV-1 or 2 PFU of ICP0- mutant (ΔICP0) HSV-1 per cell for 16 h. Wild-type and mutant HSV-1 strains expressed eYFP-ICP4, the accumulation of which was used to visualize replication compartments within cells at the edge of developing plaques (6). PIAS proteins were visualized by indirect immunofluorescence (red). Insets (dashed boxes in panel D) highlight regions of PIAS4 localization within replication compartments. (E) Confocal images show the nuclear localization of PIAS4 and SUMO2/3 within wild-type or ICP0- mutant HSV-1 replication compartments in cells infected as described above. ICP4 (green), PIAS4 (red), and SUMO2/3 (cyan) were visualized by indirect immunofluorescence. Nuclei were visualized by DAPI (blue).
Mentions: To investigate the potential significance of the accumulation of HMW SUMO-conjugated proteins during ICP0- mutant HSV-1 infection, the SUMO E3 ligase(s) that could mediate these SUMOylation events was analyzed, starting with the PIAS protein family. Consistent with other reports, PIAS proteins in HFt cells were predominantly nuclear, with microspeckled distributions characteristic of localization at matrix-associated regions (MARs) (Fig. 2A to D, mock) (65–67). While a subpopulation of PIAS1 localized to PML-NBs, substantial localization of PIAS2, PIAS3, or PIAS4 at these structures was not detected in this cell type (Fig. 2A to D, mock, and data not shown) (38, 66). PIAS4 robustly relocalized to viral replication compartments, whereas PIAS1, PIAS2, and PIAS3 did not (Fig. 2A to D). The relocalization of PIAS4 was independent of ICP0, as it occurred during wild-type or ICP0- mutant HSV-1 infection (Fig. 2D). PIAS4 is thus identified as a SUMO E3 ligase that accumulates in herpesvirus replication compartments. SUMO2/3 also accumulated in HSV-1 replication compartments, although only in the absence of ICP0 (Fig. 2E). Therefore, during ICP0- mutant HSV-1 infection, the majority of nuclear PIAS4 and SUMO2/3 localize in replication compartments.

Bottom Line: Despite characterization of the host factors that rely on SUMOylation to exert their antiviral effects, the enzymes that mediate these SUMOylation events remain to be defined.Moreover, in the absence of ICP0, high-molecular-weight SUMO-conjugated proteins do not accumulate if HSV-1 DNA does not replicate.The protein inhibitor of activated STAT (PIAS) family of SUMO ligases is predominantly associated with the suppression of innate immune signaling.

View Article: PubMed Central - PubMed

Affiliation: MRC-University of Glasgow Centre for Virus Research (CVR), Glasgow, Scotland, United Kingdom.

Show MeSH
Related in: MedlinePlus