Protein Degradation by Gammaherpesvirus RTAs: More Than Just Viral Transactivators

Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV) is a member of the Gammaherpesvirus subfamily that encodes several viral proteins with intrinsic E3 ubiquitin ligase activity or the ability to hijack host E3 ubiquitin ligases to modulate the host’s immune response and to support the viral life cycle. This review focuses specifically on how the immediate-early KSHV protein RTA (replication and transcription activator) hijacks the host’s ubiquitin–proteasome pathway (UPP) to target cellular and viral factors for protein degradation to allow for robust lytic reactivation. Notably, RTA’s targets are either potent transcription repressors or they are activators of the innate and adaptive immune response, which block the lytic cycle of the virus. This review mainly focuses on what is currently known about the role of the E3 ubiquitin ligase activity of KSHV RTA in the regulation of the KSHV life cycle, but we will also discuss the potential role of other gammaherpesviral RTA homologs in UPP-mediated protein degradation.

Analysis of the ubiquitin-modified proteome identifies novel host factors in Kaposi’s sarcoma herpesvirus lytic reactivation

“…RTA ubiquitin ligase activity has been mapped to an N-terminal RING-like domain(11). Substitution of leucine for histidine at position 145 has been shown to abolish ubiquitin ligase activity and stabilize substrates of RTA (11, 20, 37, 38). To determine whether RTA is destabilizing CDK1, HLA-C, MCM7, SUMO2/3, and VDAC1, in the context of a CURE, 18 undergraduate students transfected 293T cells with epitope tagged substrate and wild-type or mutant H145L RTA and observed substrate specific effects on stability.…”

“…RTA targets IRF7 for proteasomal degradation as a mechanism to abrogate the interferon α/β response to viral infection (11). In addition, RTA is reported to degrade a number of known RTA repressors such as ID2, MyD88, Hey1, LANA and NFκB (p65) (15)(16)(17)(18)(19)(20). This E3 ubiquitin ligase activity has been mapped to a Cys/His-rich domain between amino acids 118 and 207 of RTA (11).…”

E3 Ubiquitin Ligases in Gammaherpesviruses and HIV: A Review of Virus Adaptation and Exploitation

“…Once a threshold of RTA expression is met, viral lytic reactivation is triggered by induction of lytic gene expression [ 76 , 77 ]. During both latency and lytic reactivation, KSHV utilizes diverse methods of co-opting the host UPS to support the viral lifecycle ( Table 2 ) [ 2 , 4 , 78 ].…”

“…RTA counteracts this process by inducing K8 for degradation [ 101 ]. However, further studies are needed to confirm the degradation pathway and whether RTA is directly ubiquitinating K8 or whether RTA perhaps recruits a cellular ubiquitin ligase to facilitate its degradation [ 78 , 101 ].…”

Learning Management System (LMS) for Academic Inclusion and Learning Agency: An Interpretive Review of Technoprogressivism in ODL Instructional Technology Policy

“…It regards training and development as a viable solution to ensure that users who are unable to cope with the intricacies of such technologies are equipped with the necessary skills. It further raises a sentiment that LMSs should be designed to reflect diverse learning styles, cognitive abilities and physical attributes of students (Matarirano, Yeboah & Gqokonqana, 2021), while policies that inform their deployment must be a product of evidence-based decision-making and scientific inquiry (Combs, 2023). Given that South Africa is counted among the world's strongest distance education cultures (Qayyum & Zawacki-Richter, 2018), attention was drawn to the University of South Africa (Unisa), which is the country's only public open distance learning (ODL) institution.…”