Expanding the Known Functional Repertoire of the Human Cytomegalovirus pp71 Protein

Abstract

The human cytomegalovirus pp71 protein is packaged within the tegument of infectious virions and performs multiple functions in host cells to prime them for productive, lytic replication. Here we review the known and hypothesized functions of pp71 in regulating proteolysis, infection outcome (lytic or latent), histone deposition, transcription, translation, immune evasion, cell cycle progression, and pathogenesis. We also highlight recent advances in CMV-based vaccine candidates informed by an improved understanding of pp71 function.

A Tale of Usurpation and Subversion: SUMO-Dependent Integrity of Promyelocytic Leukemia Nuclear Bodies at the Crossroad of Infection and Immunity

“…Heterochromatin assembly results in repression of the MIEP allowing for the establishment of latency (Murphy et al, 2002;Groves et al, 2009;Sourvinos et al, 2014;Lee et al, 2015;Rauwel et al, 2015;Albright and Kalejta, 2016;Kalejta and Albright, 2020). Importantly, pp71 mutants which cannot interact with Daxx are also unable to activate an MIEP reporter (Hofmann et al, 2002), substantiating the importance of pp71-Daxx interaction for Daxx repression and transactivation from MIEP.…”

“…A pp71-null HCMV virus has a major defect in IE gene expression and productive replication (Bresnahan and Shenk, 2000;Cantrell and Bresnahan, 2006). Following infection of incompletely differentiated myeloid cells such as CD34 + hematopoietic progenitor cells (HPCs) and monocytes, pp71 remains trapped in cytoplasmic endosomes Kalejta, 2010, 2013;Kalejta and Albright, 2020). As a result, Daxx is not degraded, thereby facilitating histone deposition and assembly of repressive heterochromatin on viral genomes in conjunction with ATRX and the KAP1/SetDB1/HDAC co-repressor complex.…”

“…Although the pro-viral relevance of pp71 in initiating viral IE gene expression to induce a de novo lytic infection is well studied, importance of pp71 in mediating viral rejuvenation from latency and its role of NB remodeling in this process remains questionable (Kalejta and Albright, 2020). Interestingly, a recent report has highlighted disruption of PML NBs in a pp71-independent manner by the viral LUNA protein (Poole et al, 2018).…”

Hearing Loss Caused by HCMV Infection through Regulating the Wnt and Notch Signaling Pathways

“…The infection dysregulates Notch signaling by downregulating and altering the subcellular localization of the ligand Jag1 and effective receptor NICD1, and HCMV tegument protein pp71 has been identified to play an important role in this interaction ( Figure 3 and Table 2 ) [ 50 ]. As a multifunctional protein, pp71 regulates viral gene expression, mediates host protein proteolysis, and contributes to the viral evasion of the immune response [ 67 ]. On the other hand, HCMV infection could upregulate the expression of NICD and Notch1, which increased the proliferation of U251 glioma cells [ 68 ].…”

Functional Profile of Human Cytomegalovirus Genes and Their Associated Diseases: A Review

“…Other proteins, such as pp65 (pUL83) and pp71 (pUL82), are transported into the nucleus independently (Kalejta, 2008b). The former (pp65) contributes to viral replication, whereas the latter (pp71) mainly affects gene expression (Biolatti et al, 2018a;Kalejta and Albright, 2020). Additionally, the interaction between the pUL47/pUL48 dimer and the capsid can promote the former's transfer to the nuclear pore complex (Kalejta, 2008a).…”