Kaposi's sarcoma-associated herpesvirus-encoded LANA can induce chromosomal instability through targeted degradation of the mitotic checkpoint kinase Bub1.

[primary effusion lymphoma]

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 , Bub 1 , and the resulting degradation of Bub 1 . This interaction occurs through the Knl and kinase domains of Bub 1 , identified as important for stability and degradation . These results suggest that LANA can dysregulate Bub 1 activity , which leads to aberrant chromosome replication and aneuploidy , thus contributing to KSHV-mediated oncogenesis .T his 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 Bub 1 , a spindle checkpoint protein that is important for spindle checkpoint signaling and chromosome segregation . The downregulation of Bub 1 mediated by LANA resulted in chromosomal instability , a hallmark of cancer . We further investigated the specific domains of Bub 1 that are required for the interaction between LANA and Bub 1 . The results demonstrated that the Knl and kinase domains of Bub 1 are required for the interaction between LANA and Bub 1 . In addition , we also investigated the mechanism by which LANA promoted Bub 1 degradation . Our results showed that LANA interacted physically with the anaphase-promoting complex (APC /C ), thus promoting the degradation of Bub 1 in a ubiquitin-dependent process .

Diseases
Validation

Diseases presenting "specific domains" symptom

epidermolysis bullosa simplex

primary effusion lymphoma

You can validate or delete this automatically detected symptom