Multifaceted Roles of ICP22/ORF63 Proteins in the Life Cycle of Human Herpesviruses

Abstract

Herpesviruses are extremely successful parasites that have evolved over millions of years to develop a variety of mechanisms to coexist with their hosts and to maintain host-to-host transmission and lifelong infection by regulating their life cycles. The life cycle of herpesviruses consists of two phases: lytic infection and latent infection. During lytic infection, active replication and the production of numerous progeny virions occur. Subsequent suppression of the host immune response leads to a lifetime latent infection of the host. During latent infection, the viral genome remains in an inactive state in the host cell to avoid host immune surveillance, but the virus can be reactivated and reenter the lytic cycle. The balance between these two phases of the herpesvirus life cycle is controlled by broad interactions among numerous viral and cellular factors. ICP22/ORF63 proteins are among these factors and are involved in transcription, nuclear budding, latency establishment, and reactivation. In this review, we summarized the various roles and complex mechanisms by which ICP22/ORF63 proteins regulate the life cycle of human herpesviruses and the complex relationships among host and viral factors. Elucidating the role and mechanism of ICP22/ORF63 in virus–host interactions will deepen our understanding of the viral life cycle. In addition, it will also help us to understand the pathogenesis of herpesvirus infections and provide new strategies for combating these infections.

HSV-1 ICP22 Is a Selective Viral Repressor of Cellular RNA Polymerase II-Mediated Transcription Elongation

“…Several studies indicate that ICP22, in particular via the second and third domains, physically interacts or colocalises with host nuclear proteins [12][13][14][15][16][17]. A short sequence within the ICP22 CCR (residues 193-256) is sufficient for interaction with and inhibition of P-TEFb, a cyclin-dependent kinase complex that phosphorylates the RNA polymerase II (pol II) carboxyl-terminal domain (CTD) [11].…”

A Revision of Herpes Simplex Virus Type 1 Transcription: First, Repress; Then, Express

“…Besides its role in viral transcription, ICP22 mediates many functions, including the regulation of cellular gene transcription, the egress of capsids from the nucleus, the activities of cellular cyclin-dependent kinases, and which viral and cellular components are incorporated into the virus particle. These aspects have been reviewed elsewhere [ 82 , 145 , 146 , 151 , 152 , 153 , 154 , 155 , 156 ].…”

Identifying Protein Interactions with Viral DNA Genomes during Virus Infection

“…In the absence of ICP4, the recruitment of cellular TFIID, Mediator, and Pol II to viral DNA is significantly reduced [ 34 ]. Furthermore, ICP22 is important for the regulation of transcription elongation [ 53 , 54 ], and in the absence of ICP22 transcription elongation factors, including the FACT complex (SSRP1/Spt16), Spt5 and Spt6 have reduced association with viral DNA [ 36 ]. Taken together, iPOND data provide support for models regarding mechanisms by which viral proteins recruit host transcription machinery to viral DNA to regulate the temporal expression of viral genes.…”