Kaposi's sarcoma-associated herpesvirus-encoded LANA can induce chromosomal instability through targeted degradation of the mitotic checkpoint kinase Bub1
Authors: Hem Chandra Jha
Zhiguo Sun
Bingyi Xiao
Jie Lu
Erle S Robertson
Shuvomoy Banerjee
Journal: Journal of Virology (2014)
Discipline: MICROBIOLOGY
Keywords: Kaposi's sarcoma-associated herpesvirus; KSHV; LANA; chromosomal instability; Bub1
Affiliations: Department of Microbiology and Tumor Virology Program, Abramson Comprehensive Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA., Department of Microbiology and Tumor Virology Program, Abramson Comprehensive Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA .

Abstract:  Kaposi's sarcoma-associated herpesvirus (KSHV) has a significant contributory role in the development of three major human neoplastic or lymphoproliferative diseases: Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). These diseases are associated with chromosomal instability, a hallmark of human cancer. The latency-associated nuclear antigen (LANA) encoded by KSHV plays a key role in regulating a number of cellular pathways critical for oncogenesis. KSHV LANA alone can induce the development of B-cell hyperplasia and lymphoma in mice expressing LANA. LANA also induces chromosomal instability, thus promoting oncogenesis. However, the precise mechanism underlying LANA-mediated chromosomal instability remains uncharted. Here we report that LANA promoted the induction of chromosomal instability and the formation of micronuclei and multinucleation through its interaction with one of the critical spindle checkpoint proteins, Bub1, and the resulting degradation of Bub1. This interaction occurs through the Knl and kinase domains of Bub1, identified as important for stability and degradation. These results suggest that LANA can dysregulate Bub1 activity, which leads to aberrant chromosome replication and aneuploidy, thus contributing to KSHV-mediated oncogenesis. Importance: This work represents the first set of results identifying a novel mechanism by which LANA, a latency-associated antigen encoded by KSHV, can induce the degradation of Bub1, a spindle checkpoint protein that is important for spindle checkpoint signaling and chromosome segregation. The downregulation of Bub1 mediated by LANA resulted in chromosomal instability, a hallmark of cancer. We further investigated the specific domains of Bub1 that are required for the interaction between LANA and Bub1. The results demonstrated that the Knl and kinase domains of Bub1 are required for the interaction between LANA and Bub1. In addition, we also investigated the mechanism by which LANA promoted Bub1 degradation. Our results showed that LANA interacted physically with the anaphase-promoting complex (APC/C), thus promoting the degradation of Bub1 in a ubiquitin-dependent process. 

Retracted: No

PubPeer comments:
 Figure 1. * Red boxes: The GFP panel in Figure 1C shares unexpected similarities with the middle GAPDH panel in Figure 1E. Reported to the journal in 2017. Of renewed interest because of recent other Pubpeer comments on papers from this group: https: pubpeer.com search?q=erle+robertson ![file] Here is a close-up of both panels, with the contrast enhanced to bring out the details. ![file] Could the authors please comment? , 
 Last author appears to be on this journalu2019s editorial board: https: jvi.asm.org content board-editors , 
 These concerns were shared with the journal in July 2017, but no correction or other action as of today. ,