Protein interactions critical for hepatitis B virus replication and mycobacterial growth

0567305 - ÚOCHB 2023 RIV CZ eng A - Abstract
Pichová, Iva
Protein interactions critical for hepatitis B virus replication and mycobacterial growth.
Czech Chemical Society Symposium Series. Roč. 20, č. 6 (2022), s. 348-348. ISSN 2336-7202.
[Annual meeting of the National Institute of Virology and Bacteriology (NIVB) /1./. 30.11.2022-02.12.2022, Kutná Hora]
R&D Projects: GA MŠMT(CZ) LX22NPO5103
Institutional support: RVO:61388963
Keywords : hepatitis B * HBx protein * antiviral
OECD category: Virology
http://www.ccsss.cz/index.php/ccsss/issue/view/37/67

Hepatitis B is a liver infection caused by the hepatitis B virus (HBV), a member of the familyHepadnaviridae.HBV can induce both acute and chronic disease and is a major global health problem. Although the chronic infection is mostly asymptomatic, it can lead to cirrhosis and hepatocellular carcinoma (HCC) development. Despite intensive research of HBV, little is known about the regulations of molecular mechanisms of HBV replication, cccDNA formation and degradation, HCC development, and about the reactivation of HBV. These mechanisms include a series of interactions of HBV proteins, genomic DNA, ccc DNA with host cell machineries. The genome of HBV consists of circular partially double-stranded DNA, which is approximately 3.2 kb and contains only four open reading frames (C, P, S, and X) that largely overlap and encode multiple proteins using different in-frame start codons1. The smallest intrinsically disordered protein HBx exerts its activities by interacting with a large number of cellular partners that are located either in the cytoplasm or in the nucleus. HBx is involved in multiple functions including gene transcription, intracellular signal transduction, cell proliferation, apoptotic cell death, and DNA repair. Currently, the main HBx role is attributed to activation of HBV transcription through interaction with the host DNA damage-binding protein (DDB1) E3 ubiquitin ligase and following targeting of the HBV transcription restriction Smc5/6 complex for degradation in proteasome2,3.Blocking of interactions between HBx-DDB1 and Smc5/6 represents thus promising target for specific inhibitor development. However, any details about these interactions are not currently known. Our project is focused on analysis of HBx protein interactions with components of Smc5/6 complex and on mechanism of HBx transcription regulation and viral replication. We also search for further cellular proteins interactiong with HBx and precore protein.Mycobacterium tuberculosis(Mtb) is associated with millions of deaths per year. Tuberculosis is one of the top ten causes of death. Treatment of mycobacterial infections is complicated by increased prevalence of multidrug-resistant and extensively drug-resistant Mtb strains as well as by development of persistent infection. Despite global research efforts and investments, mechanisms underlying pathogenesis, virulence and persistence of Mtb infection remain poorly understood. Currently used drugs do not target latent infection and are less effective against drug resistant TB. The discovery of new types of small molecule inhibitors with new modes of action is increasingly urgent. Purines nucleotides, the substrates of nucleic acids, coenzymes, allosteric modulators and energy intermediate represent promising targets for development of novel inhibitor types. All enzymes from purine biosynthetic cascades are known in mycobacteria however, essentiality of particular enzymes and regulation of purine metabolism under normal and stress conditions are not completely understood. We investigate transcription regulation of the purine metabolism under normal growthconditions, hypoxia and nutrient starvation using transcriptome analysis, promoter reporter assay and other techniques. Project is further focused on possible formation of a purinosome, a complex formed from de novopurine biosynthetic enzymes, which can facilitate metabolic flux and minimize the escape of reactive and unstable intermediates in a model species Mycobacterium smegmatis. Identification and validation of essential enzymes from purine biosynthesis will identify new targets for inhibitor development.
Permanent Link: https://hdl.handle.net/11104/0338565