Degradation of the viral proteins in infected cells is a way to avoid their aberrant accumulation, on one hand, and generate viral peptides, which will be presented at cell surface by the major histocompatibility complex, raising an immune response, on the other hand. In the case of HBV infection, accumulation of mutant viral proteins within the endoplasmic reticulum can result in a particular phenotype, characterised by a ground glass appearance of hepatocytes.
Endoplasmatic reticulum (ER) associated protein degradation - ERAD is an important cellular process for maintaining cellular homeostasis. Aberrant accumulation of poorly folded or aggregated proteins in ER, either endogenous or resulted from viral infection and replication, can have serious consequences on cell integrity. Mutations at the level of the human hepatitis B virus (HBV) DNA, coding for the envelope proteins, have been recently described in chronically infected patients. These genetic alterations result in accumulation the viral proteins within the ER of the infected cells associated with a ground glass-like aspect of the hepatocytes (GGH). GGH are currently considered markers of chronic HBV infection and are often associated with early development of liver cirrhosis or hepatocellular carcinoma; however, the molecular bases of these pathologies are still unknown. Envelope proteins accumulation and absence of degradation, could also be a strategy adopted by HBV to prevent exposure of viral peptides to the cell surface, in association with the major histocompatibility complex I, thus avoiding an immune response. The project aims to investigate the mechanism by which the HBV envelope proteins and the ER-associated functions modulate each other and to identify cellular factors involved in viral degradation. The study involves comparative analysis of three experimental models of clinical relevance and their interaction with specific cellular proteins of the ERAD network: a) the wild-type proteins, characterised by a long half-life and partial degradation; b) proteins containing mutations at the preS1/preS2 regions, characterised by the lack of degradation, ER accumulation and induction of the GGH phenotype and c) short-lived proteins, characterised by accelerated degradation. Understanding the mechanism of viral protein degradation is important for developing new therapeutic strategies and alleviate the severe pathology in infections with mutant HBV strains.
Scientific Researcher II
Catalin Lazar is a researcher in the Institute of Biochemistry of the Romanian Academy. Catalin is currently working in Viral Glycoproteins in the Viral Glycoproteins.
Romanian Academy