Preprint
DISTINCT ROLES OF VIRAL US3 AND UL13 PROTEIN KINASES IN HERPES VIRUS SIMPLEX TYPE 1 (HSV-1) NUCLEAR EGRESS
bioRxiv : the preprint server for biology
03/21/2023
DOI: 10.1101/2023.03.20.533584
PMCID: PMC10055267
PMID: 36993506
Abstract
Herpesviruses transport nucleocapsids from the nucleus to the cytoplasm by capsid envelopment into the inner nuclear membrane and de-envelopment from the outer nuclear membrane, a process that is coordinated by nuclear egress complex (NEC) proteins, pUL34, and pUL31. Both pUL31 and pUL34 are phosphorylated by the virus-encoded protein kinase, pUS3, and phosphorylation of pUL31 regulates NEC localization at the nuclear rim. pUS3 also controls apoptosis and many other viral and cellular functions in addition to nuclear egress, and the regulation of these various activities in infected cells is not well understood. It has been previously proposed that pUS3 activity is selectively regulated by another viral protein kinase, pUL13 such that its activity in nuclear egress is pUL13-dependent, but apoptosis regulation is not, suggesting that pUL13 might regulate pUS3 activity on specific substrates. We compared HSV-1 UL13 kinase-dead and US3 kinase-dead mutant infections and found that pUL13 kinase activity does not regulate the substrate choice of pUS3 in any defined classes of pUS3 substrates and that pUL13 kinase activity is not important for promoting de-envelopment during nuclear egress. We also find that mutation of all pUL13 phosphorylation motifs in pUS3, individually or in aggregate, does not affect the localization of the NEC, suggesting that pUL13 regulates NEC localization independent of pUS3. Finally, we show that pUL13 co-localizes with pUL31 inside the nucleus in large aggregates, further suggesting a direct effect of pUL13 on the NEC and suggesting a novel mechanism for both UL31 and UL13 in the DNA damage response pathway. IMPORTANCE Herpes simplex virus infections are regulated by two virus-encoded protein kinases, pUS3 and pUL13, which each regulate multiple processes in the infected cell, including capsid transport from the nucleus to the cytoplasm. Regulation of the activity of these kinases on their various substrates is poorly understood, but importantly, kinases are attractive targets for the generation of inhibitors. It has been previously suggested that pUS3 activity on specific substrates is differentially regulated by pUL13 and, specifically, that pUL13 regulates capsid egress from the nucleus by phosphorylation of pUS3. In this study, we determined that pUL13 and pUS3 have different effects on nuclear egress and that pUL13 may interact directly with the nuclear egress apparatus with implications both for virus assembly and egress and, possibly, the host cell DNA- damage response.
Details
- Title: Subtitle
- DISTINCT ROLES OF VIRAL US3 AND UL13 PROTEIN KINASES IN HERPES VIRUS SIMPLEX TYPE 1 (HSV-1) NUCLEAR EGRESS
- Creators
- Masoudeh Masoud Bahnamiri - University of IowaRichard J Roller - University of Iowa
- Resource Type
- Preprint
- Publication Details
- bioRxiv : the preprint server for biology
- DOI
- 10.1101/2023.03.20.533584
- PMID
- 36993506
- PMCID
- PMC10055267
- Language
- English
- Date posted
- 03/21/2023
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984381023702771
Metrics
4 Record Views