Journal: bioRxiv

Article Title: Proteasomal Inhibition Triggers Viral Oncoprotein Degradation via Autophagy-Lysosomal Pathway

doi: 10.1101/780171

Figure Lengend Snippet: Due to uncontrolled cell proliferation, cancer cells often encounter excess mis-/un-folded protein aggregates, which are subsequently labeled with either K48-linked or K63-linked polyubiquitination for proteolytic degradation. While K48-linked ubiquitin chains are targeted for the proteasomal pathway, K63-linked directs autophagy mediated protein degradation. Upon proteasomal inhibition, EBV oncoprotein EBNA3C is predominantly tagged with K63-linked polyubiquitin chains, translocated to cytoplasm by an unknown mechanism and degraded through autophagy-lysosomal pathway. The N-terminal domain plays a central role in EBNA3C’s degradation through autophagy mechanism by participating within the p62-LC3B complex. Suppression of autophagy pathway (Beclin1 knockdown or chloroquine, CQ treatment) reverses EBNA3C degradation in response to proteasomal inhibition. Additionally, proteasomal inhibitors (such as MG132) induce both autophagy and viral gene transcription that eventually activate viral lytic replication. The results provide foundation to exploit proteasome inhibitors as potential therapeutic approach for EBV associated B-cell lymphomas, where EBNA3C is expressed, typically diagnosed in immunocompromised individuals.

Article Snippet: Rabbit monoclonal antibodies directed against LC3A/B (Clone# D3U4C), K48-linkage specific polyubiquitin (D9D5) and K63-linkage specific polyubiquitin (D7A11) were purchased from Cell Signaling Technology Inc. (Danvers, MA, USA).

Techniques: Labeling, Inhibition