Tale of a tegument transactivator: the past, present and future of human CMV pp71

Abstract

Herpesviruses assemble large virions capable of delivering to a newly infected cell not only the viral genome, but also viral proteins packaged within the tegument layer between the DNA-containing capsid and the lipid envelope. In this review, we describe the tegument transactivator of the β-herpesvirus human CMV, the pp71 protein. We present the known mechanistic features through which it activates viral gene expression during a lytic infection but fails to do so when the virus establishes latency, and describe how pp71 stimulates the cell cycle and may help infected cells avoid detection by the adaptive immune system. A historical overview of pp71 is extended with current perceptions of its roles during human CMV infections and suggestions for future avenues of experimentation.

Figure 1. The UL82 locus

Schematic diagram of the prototypic human CMV genome with an expansion of the region surrounding UL82 (shown, for simplicity, in reverse orientation to its arrangement in the genome). Annotated open reading frames are shown as block arrows. mRNAs are shown as wavy lines with a C and a AAA, with their size is indicated in kilobase pairs. The deletion made in UL82 to construct the pp71-null virus is indicated. AAA: 3´ poly-A tail; C: 5´ cap; IRL: Internal repeat long; IRS: Internal repeat short; TRL: Terminal repeat long; TRS: Terminal repeat short; UL: Unique long; US: Unique short.

Figure 2. Sequence features of pp71

A linear representation of the 559-amino acid pp71 protein. Locations of the known post-translational modification (i.e., phosphorylation) sites are indicated (S and T). Domains of the protein representing a likely structural scaffold (dUTPase-related domain, amino acids 266–365) or controlling subcellular localization (mid-region, amino acids 94–300) are indicated. Motifs that mediate the interactions with Daxx (Daxx interaction domain 1, amino acids 206–213; Daxx interaction domain 2, amino acids 324–331) and the Rb family proteins (LXCXD, amino acids 216–220) are also depicted. Rb: Retinoblastoma; S: Serine; T: Threonine.

Figure 3. The subcellular localization of tegument-delivered pp71 influences the outcome of viral infection

Upon entry, HCMV virions (top) introduce tegument proteins into infected cells. In differentiated cells such as fibroblasts (left), tegument-delivered pp71 enters the nucleus and induces the degradation of Daxx and BclAF1, and displaces HDACs and ATRX. This inactivates the intrinsic defense instated by these proteins, activates IE gene expression and initiates productive, lytic viral replication. In undifferentiated cells such as CD34⁺ cells (right), tegument-delivered pp71 is cytoplasmic and Daxx is not degraded. The intrinsic defense is able to silence IE gene expression, and latency is established. While it is likely that BclAF1 and ATRX (depicted as transparent) also restrict viral gene expression during latency, this has not been demonstrated experimentally. HCMV: Human CMV; HDAC: Histone deacetylase; IE: Immediate–early; MIEP: Major immediate–early promoter.

Figure 4. Timeline of pp71 activities during lytic infection

Known functions of pp71 are temporally placed within the time course of a human CMV infection. E: Early; IE: Immediate–early; L: Late.

Figure 5. Historical timeline of pp71

Beginning with its identification in virions and ending with the recent identification of an additional cellular target of pp71-mediated degradation (BclAF1), this timeline highlights significant advancements during the history of pp71 research. DID: Daxx interaction domain; IE: Immediate–early; MIEP: Major immediate–early promoter; PML-NB: Promyelocytic leukemia nuclear body; Rb: Retinoblastoma; VP: Virion protein.