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Review
. 2021 Feb 1:10:607526.
doi: 10.3389/fcimb.2020.607526. eCollection 2020.

The Fate of Speckled Protein 100 (Sp100) During Herpesviruses Infection

Mila Collados Rodríguez  1
Affiliations
Review

The Fate of Speckled Protein 100 (Sp100) During Herpesviruses Infection

Mila Collados Rodríguez. Front Cell Infect Microbiol. .

Abstract

The constitutive expression of Speckled-100 (Sp100) is known to restrict the replication of many clinically important DNA viruses. This pre-existing (intrinsic) immune defense to virus infection can be further upregulated upon interferon (IFN) stimulation as a component of the innate immune response. In humans, Sp100 is encoded by a single gene locus, which can produce alternatively spliced isoforms. The widely studied Sp100A, Sp100B, Sp100C and Sp100HMG have functions associated with the transcriptional regulation of viral and cellular chromatin, either directly through their characteristic DNA-binding domains, or indirectly through post-translational modification (PTM) and associated protein interaction networks. Sp100 isoforms are resident component proteins of promyelocytic leukemia-nuclear bodies (PML-NBs), dynamic nuclear sub-structures which regulate host immune defenses against many pathogens. In the case of human herpesviruses, multiple protein antagonists are expressed to relieve viral DNA genome transcriptional silencing imposed by PML-NB and Sp100-derived proteinaceous structures, thereby stimulating viral propagation, pathogenesis, and transmission to new hosts. This review details how different Sp100 isoforms are manipulated during herpesviruses HSV1, VZV, HCMV, EBV, and KSHV infection, identifying gaps in our current knowledge, and highlighting future areas of research.

Keywords: ISG; PML-NB; Sp100; epigenetics; herpesviruses; immunity.

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Conflict of interest statement

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Sp100 isoform domain composition. Sp100A/B/C/high mobility group (HMG) share domain architecture within their first 477 amino acid (aa) residues: dimerization and promyelocytic leukemia-nuclear body (PML-NB) targeting (aa 3–152, pink), destruction-box (D-box, aa 165–168, teal); HP1 interacting region (aa 287–334, orange) encompassing a SUMO consensus motif (SCM) with Lys297 SUMO modification (K297, yellow pin) and SUMO-interacting motif (SIM, aa 323–326, black half-moon); trans-activating region (TR, aa 333–407, cherry); autoepitopes are indicated with vertical numbers in ochre below HP1 and TR segments (see EBV section); nuclear localization sequence (NLS, aa 440–450, purple). Sp100B/C/HMG are identical up to aa 685, which includes the high mobility group (HMG) 2 (aa 477–528, fern) and Sp100, AIRE-1, NucP41/75, DEAF-1 (SAND, aa 603-676, sand) DNA-binding domains. Sp100HMG contains two additional HMG (HMG1, aa 682–754; HMG2, aa 768–838) domains and a coiled coil (CC, aa 843–879, mint) domain. Sp100C contains a plant homeodomain (PHD, aa 696-754, green) and bromodomain (BRD, aa 762–878, light green) domain. C-terminal domain features are described in Table 1. Numbers indicate the positions of aa with each isoform. UniProt IDs: Sp100A, P23497-2; Sp100B, P23497-3; Sp100C, P23497-4; Sp100HMG, P23497-1. Further details on the Sp100 gene locus (ENSG00000067066) can be found at ENSEMBL1.
Figure 2
Figure 2
General epigenetic mechanisms influencing chromatin binding properties of Sp100. (A) Histone modifier enzymes sorted as “writers” (blue arrow) or “erasers” (red arrow) that influence the acetylation (orange teardrop), methylation (gray teardrop) or phosphorylation (yellow teardrop) post-translational modification (PTM) status of histones exemplified here through H3 tail (green line, not to scale). (B) Models for direct (SAND, HMG) and indirect (HP1, BRD, PHD) DNA binding properties of Sp100 isoforms; (i) dimerized HP1s (orange ovals) bind HMT (gray oval) leading to histone H3K9 trimethylation (gray teardrop) of consecutive nucleosomes (lilac). A red question mark indicates whether Sp100B/C/high mobility group (HMG) binds DNA (dark blue string) and/or HP1 as a monomer or as a dimer; (ii) Sp100 can potentially homo- (circular back arrows) and heterodimerize (double head black arrows) depending on the isoform expression profile and subnuclear localization. Sp100 color code refers to Figure 1 characteristic features; (iii) examples of histone readers’ regulation. H3K4me1-3 inhibits (red flat tip arrows) the binding of Sp100C, Sp140 and HP1 to histone 3, while H3K9me3 promotes (light blue arrows) Sp100C and HP1 binding. Different kinases drive the “phospho-switches” that influence Sp100C, Sp140 and HP1 binding to histone 3 (H3pT3/S10/T6); (iv) histone 3 tail (aa 1–31) highlighting aa and PTMs discussed in the main text associated with the epigenetic silencing of viral DNA and reactivation from latency. (C) Viral and epigenetic factors that influence HSV1 transcription; vertical empty arrow pointing down the H3 tail shows an example of post-translational modifications (PTMs) associated with reactivation from latency where the c-Jun N-terminal kinase (JNK) phosphorylates the aa residues next to H3K9/27me3, known as “methyl-phospho switch”, a first step in chromatin relaxation. The participation of Sp100 variants as histone readers in each phase remains to be clearly further detailed (black question mark).
Figure 3
Figure 3
Sp100 interactors and herpesvirus counteractors. Outer circle, herpesviruses proteins (HSV1, ICP0; VZV, ORF61p; HCMV, IE1/p72; EBV, EBNA-LP; KSHV, LANA, and ORF75) that antagonize Sp100. Inner circle, network of Sp100 related protein interactions likely to be disrupted during herpesvirus infection. Clustered networks of known Sp100 interactors shaded in blue. Interactions retrieved from BioGRID (Stark et al., 2006), minimum experimental evidence from two independent studies.
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