Journal
JOURNAL OF VIROLOGY
Volume 95, Issue 23, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.01459-21
Keywords
KSHV; lytic; ORF45; p53; TP53; USP7; HAUSP; primary effusion lymphoma; PEL; ubiquitination
Categories
Funding
- Public Health Service (PHS) [CA019014, DE018304, CA016086]
Ask authors/readers for more resources
KSHV utilizes ORF45 as a novel inhibitor to disrupt p53 signaling, resulting in decreased p53 activity, cytoplasmic localization of p53, and reduced nuclear transcriptional activity.
Kaposi sarcoma-associated herpesvirus (KSHV) is a carcinogenic double stranded DNA virus and the etiological agent of Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). To prevent premature apoptosis and support its replication cycle, KSHV expresses a series of open reading frames (ORFs) that regulate signaling by the p53 tumor suppressor protein. Here, we describe a novel viral inhibitor of p53 encoded by KSHV ORF45 and identify its mechanism of action. ORF45 binds to p53 and prevents its interactions with USP7, a p53 deubiquitinase. This results in decreased p53 accumulation, localization of p53 to the cytoplasm, and diminished transcriptional activity. IMPORTANCE Unlike in other cancers, the tumor suppressor protein p53 is rarely mutated in Kaposi sarcoma (KS). Rather, Kaposi sarcoma-associated herpesvirus (KSHV) inactivates p53 through multiple viral proteins. One possible therapeutic approach to KS is the activation of p53, which would result in apoptosis and tumor regression. In this regard, it is important to understand all the mechanisms used by KSHV to modulate p53 signaling. This work describes a novel inhibitor of p53 signaling and a potential drug target, ORF45, and identifies the mechanisms of its action.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available