Crosstalk between Proteasomal and  Lysosomal Protein Degradation Pathway in  EBV-Induced B-cell Lymphomas

Crosstalk between Proteasomal and Lysosomal Protein Degradation Pathway in EBV-Induced B-cell Lymphomas

dc.contributor.advisor	Saha, Abhik
dc.creator.researcher	Gain, Chandrima
dc.date.accessioned	2024-07-16T09:35:57Z
dc.date.available	2024-07-16T09:35:57Z
dc.description.abstract	Epstein-Barr virus (EBV) nuclear oncoprotein EBNA3C plays an important role during B-cell transformation and subsequent development of several B-cell lymphomas specifically in those who are from immuno-compromised background. EBNA3C manipulates several important cellular pathways including ubiquitin-proteasome machinery and deregulate multiple cellular oncoproteins and tumor suppressor proteins. Studies have revealed that EBNA3C is ubiquitinated at its N-terminal domain and can interact with 20S proteasome machinery. However, In vitro, the viral protein is extremely stable in EBV transformed growing B-lymphocytes. EBNA3C can also bypass autophagy-lysosomal mediated protein degradation and subsequent antigen presentation for T-cell recognition. Moreover, recently, our group demonstrated that in response to metabolic stress, EBNA3C elevates the basal level of autophagy through epigenetic alternation and transcriptional activation of several autophagy related genes (ATGs). This also serves as a prerequisite for B-cell survival under growth limiting conditions. The crosstalk between EBNA3C mediated proteasomal and autophagy-lysosomal machinery further prompted us to investigate the underlying proteolytic mechanism governing EBNA3C’s turn-over. We demonstrate that proteasomal inhibition accelerates EBNA3C degradation both in EBV transformed B-lymphocytes and ectopic-expression systems. Interestingly, in presence of proteasomal inhibitors, two EBNA3 family oncoproteins–EBNA3A and EBNA3C were degraded, but not the viral tumor suppressor protein EBNA3B. EBNA3C degradation induced by proteasomal inhibition is partially blocked when autophagy-lysosomal pathway is inhibited. In response to proteasomal inhibition, EBNA3C is predominantly K63-linked polyubiquitinated and colocalized with the autophagy-lysosomal fraction in the cytoplasm and participated within p62-LC3B complex, thus facilitating autophagy-mediated degradation. We further describe that the degradation signal is located at the first 50 residues of the N-terminal domain of EBNA3C. The colony formation ability of this important viral oncoprotein is also reduced when proteasome is blocked. In addition, proteasomal inhibition induces apoptotic cell death and accelerates transcriptional activation of both latent and lytic gene expression which further induces viral reactivation from EBV transformed B-lymphocytes. Overall, this study provides rationale to use proteasome inhibitors as potential therapeutic strategy against multiple EBV associated B-cell lymphomas.	en_US
dc.description.searchVisibility	true	en_US
dc.format.mimetype	application/pdf	en_US
dc.identifier.uri	https://www.presiuniv.ac.in	en_US
dc.identifier.uri	http://www.presiuniv.ndl.iitkgp.ac.in/handle/123456789/2387
dc.language.iso	eng	en_US
dc.rights.accessRights	authorized	en_US
dc.source	Presidency University	en_US
dc.source.uri	https://www.presiuniv.ac.in	en_US
dc.subject	Epstein-Barr virus	en_US
dc.subject	Life Sciences	en_US
dc.subject	Microbiology	en_US
dc.title	Crosstalk between Proteasomal and Lysosomal Protein Degradation Pathway in EBV-Induced B-cell Lymphomas	en_US
dc.type	text	en_US