Protein kinases conserved in herpesviruses potentially share a function mimicking the cellular protein kinase cdc2

Abstract

Herpesviruses encode protein kinases. A subset of these proteins, represented by HSV-1 UL13, are conserved throughout all members of the Herpesviridae, and here, are designated CHPKs (conserved herpesvirus protein kinases). In addition to conserved gene products like CHPKs, herpesviruses encode genes specific to respective herpesviruses. When acting upon conserved viral gene products or cellular factors, CHPKs may play conserved roles in the life cycles of herpesviruses. CHPKs may also express unique functions within the infectious process of individual herpesviruses when specific viral gene products are targeted. CHPKs demonstrate specific activity in multiple herpesvirus infections, functioning in the regulation of viral gene expression in HSV-1, tissue tropism in VZV, and viral DNA synthesis, encapsidation and egress from the nucleus in HCMV. The HCMV CHPK, however, can partially substitute for the HSV-1 CHPK. Representative CHPKs from all Herpesviridae subfamilies can also facilitate the hyperphosphorylation of the cellular translation factor, EF-1delta. This indicates that CHPKs have conserved functions. Recent data have shown that both CHPKs and a cellular protein kinase, cdc2, phosphorylate the same amino acid residues of target proteins. Thus, CHPKs may mimic cdc2 function in infected cells.

Viral Serine/Threonine Protein Kinases

“…Although the kinase is conserved among herpesviruses, CHPK from different herpesvirus subfamilies show considerable variation in amino acid sequence. Although some sequence preferences for substrate specificity have been described for individual CHPK, there is no consensus phosphorylation sequence for all CHPK (10,30,95,96,100). Despite these differences, partial functional conservation has been reported (193).…”

ORF36 Protein Kinase of Kaposi's Sarcoma Herpesvirus Activates the c-Jun N-terminal Kinase Signaling Pathway

“…Previous work demonstrated that ␣-, ␤-, and ␥-herpesviruses encode viral protein kinases, which are represented by HSV-1 ULl3, VZV ORF47, human cytomegalovirus UL97, human herpesvirus-6 U69, EBV EGLF4, KSHV ORF36, and rhesus rhadinovirus ORF36 (5,42,43). Similar to cellular serine/threonine protein kinases, these viral kinases contain 11 subdomains; a conserved lysine residue in subdomain II was important for kinase activity (44,45).…”

“…VZV ORF47 null mutants show replication deficiency and the inability to phosphorylate several viral proteins (15,49,50). In addition to phosphorylating viral targets, cellular targets including casein kinase II ␤, EF-1␦, p60, and RNA polymerase II serve as substrates for herpesvirus protein kinases (5,42,(51)(52)(53). Demonstrating conserved function between herpesvirus protein kinases, chimeric viruses expressing substituted protein kinases from other herpesviruses are partially able to compensate for lost function (54).…”

“…Recent studies have revealed that mutation of a conserved lysine residue within subdomain II abolishes phosphorylation; this finding shows that this region is necessary for the catalytic activity of these protein kinases (6,7). The protein kinases of herpesviruses appear to mimic the function of cellular protein kinases, including Cdc2 and cellular translational factor EF-1␦, by phosphorylating the same amino acid residues on their cognate protein targets (5,8). Furthermore the viral protein kinases are associated with the virion and may promote dissociation and entry of the virus particle by phosphorylating the viral tegument proteins (9 -12).…”

A viral kinase mimics S6 kinase to enhance cell proliferation

“…These viruses commandeer host cell machinery to synthesize viral proteins needed for successful replication. For example, UL13 and UL97, orthologous kinases encoded by herpes simplex type I (HSV1) and human cytomegalovirus (HCMV), respectively, are functionally similar to the cellular kinase CDC2/CDK1 and phosphorylate several cellular functional targets of cyclin-dependent kinases, including elongation factor 1δ (EF1δ) (29) and pRB (30). Herpesviral kinases are also known to phosphorylate several different members of the cellular DNA damage response pathway.…”