The chaperone dynein LL1 mediates cytoplasmic transport of empty and mature hepatitis B virus capsids

Osseman, Quentin; Gallucci, Lara; Au, Shelly; Cazenave, Christian; Berdance, Elodie; Blondot, Marie-Lise; Cassany, Aurélia; Bégu, Dominique; Ragues, Jessica; Aknin, Cindy; Sominskaya, Irina; Dishlers, Andris; Rabe, Birgit; Anderson, Fenja; Panté, Nelly; Kann, Michael

doi:10.1016/j.jhep.2017.10.032

Cited by 25 publications

(26 citation statements)

References 46 publications

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“…Moreover, the heat shock protein A4 (HSPA4) expression is upregulated in patients affected by hepatitis B virus (HBV)-related hepatocellular carcinoma [48], in particular in those with earlier recurrence. The chaperone dynelin LL1 (DYNLL1) has an essential role in the cytoplasmic translocation of hepatitis B viral caspide [49]. All of these reasons make these proteins important targets for the development of new antiviral agents.…”

Section: High Degree Centrality Gene Study and Potential Drug Therapymentioning

confidence: 99%

In Silico Discovery of Candidate Drugs against Covid-19

Cava

Bertoli

Castiglioni

2020

Viruses

171

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Previous studies reported that Angiotensin converting enzyme 2 (ACE2) is the main cell receptor of SARS-CoV and SARS-CoV-2. It plays a key role in the access of the virus into the cell to produce the final infection. In the present study we investigated in silico the basic mechanism of ACE2 in the lung and provided evidences for new potentially effective drugs for Covid-19. Specifically, we used the gene expression profiles from public datasets including The Cancer Genome Atlas, Gene Expression Omnibus and Genotype-Tissue Expression, Gene Ontology and pathway enrichment analysis to investigate the main functions of ACE2-correlated genes. We constructed a protein-protein interaction network containing the genes co-expressed with ACE2. Finally, we focused on the genes in the network that are already associated with known drugs and evaluated their role for a potential treatment of Covid-19. Our results demonstrate that the genes correlated with ACE2 are mainly enriched in the sterol biosynthetic process, Aryldialkylphosphatase activity, adenosylhomocysteinase activity, trialkylsulfonium hydrolase activity, acetate-CoA and CoA ligase activity. We identified a network of 193 genes, 222 interactions and 36 potential drugs that could have a crucial role. Among possible interesting drugs for Covid-19 treatment, we found Nimesulide, Fluticasone Propionate, Thiabendazole, Photofrin, Didanosine and Flutamide.While the diagnosis of COVID-19 is based on the amplification of the viral genome in real-time PCR with specific probes, the current treatment of affected individuals is limited to a mixture of a broad-spectrum of antiviral drugs [6]. However, in many cases this pharmacological approach has proven to be totally ineffective.Screening drug studies on pangolin SARS-CoV-2, which is the human-related Coronavirus, demonstrated that three drugs (cepharanthine, selamectin and mefloquine hydrochloride) were effective in inhibiting viral replication, with cepharanthine potently inhibiting coronavirus infection at viral entry and post-entry viral replication [7]. The last drug is an anti-inflammatory and antineoplastic alkaloid approved for leukopenia and it is also proposed to inhibit the human immunodeficiency virus type 1 (HIV) entering in cells by reducing plasma membrane fluidity. In humans, it has a reduced toxicity.Mefloquine is the approved treatment for malaria and has antiviral activity against both MERS-CoV and SARS-CoV [8]. The antiviral mechanism of selamectin is still unknown, as it is used usually as a topical broad-spectrum parasiticide in little animals (e.g., cats and dogs).The entry of the virus in the cells is mediated by spike (S) glycoprotein; in particular, the spike 1 (S1) surface unit allows the attachment of the virus to cellular receptors. To allow the entry of the viral particles, the S protein is cleaved by cellular proteases at the S1/S2 and the S2 site. Then, the viral capside is fused with the cellular membrane, a process driven by the S2 subunit [9]. It has been described that SARS-CoV entrance is ...

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Section: High Degree Centrality Gene Study and Potential Drug Therapymentioning

confidence: 99%

In Silico Discovery of Candidate Drugs against Covid-19

Cava

Bertoli

Castiglioni

2020

Viruses

171

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“…Several virus encoded proteins have also been shown to bind to DLC [89][90][91]. Viruses have been proposed to exploit the DLC mediated cargo machinery for their efficient nuclear translocation and replication.…”

Section: Dlc: a Nanny Protein For Bim And Bmf?mentioning

confidence: 99%

The established and the predicted roles of dynein light chain in the regulation of mitochondrial apoptosis

2018

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The mitochondrial pathway of apoptosis is regulated by the interplay between the members of Bcl-2 family. Within this family, BH3-only proteins are the sensors of apoptotic stimuli and can trigger apoptosis either by inhibiting the anti-apoptotic Bcl-2-family proteins or by directly activating the effectors Bax and Bak. An expanding body of research suggests that a number of non-Bcl-2 proteins can also interact with Bcl-2 proteins and contribute to the decision of cell fate. Dynein light chain (LC8, DYNLL or DLC), a hub protein and a dimerizing engine has been proposed to regulate the pro-apoptotic activity of two BH3-only proteins, Bim and Bmf. Our recent work has provided insight into the mechanisms through which DLC1 (DYNLL1) modulates Bim activity. Here we discuss the present day understanding of Bim-DLC interaction and endeavor to evaluate this interaction in the light of information from studies of DLC with other binding partners.

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“…Studies have shown that the destabilization of microtubules with nocodazole blocks the import of the HBV capsid, as well as the related virus duck hepatitis B virus (DHBV) [ 40 , 41 ]. Recently, the group of M. Kann further confirmed the requirement of a microtubule for HBV nuclear trafficking, and showed that the HBV capsid uses the dynein motor complex for nuclear trafficking via an interaction with the dynein light chain LL1 [ 42 ].…”

Section: Intracellular Transport and Nuclear Importmentioning

confidence: 99%

“…Guo has observed the presence of DNase1-sensitive nucleocapsids (indicative of a more unstable/partially disassembled capsids) in the cytoplasm. The large majority of these capsids, according to their results, contain deproteinated rcDNA (dprcDNA), which they consider to be the precursor of cccDNA [ 42 , 59 , 60 ]. They suggest that the maturation processes inside the capsid (completion of the (+) strand DNA and the removal of the polymerase) in the cytoplasm lead to structural changes, allowing the exposure of the capsid NLS and nuclear import [ 46 ].…”

Section: Intracellular Transport and Nuclear Importmentioning

confidence: 99%

Early Steps of Hepatitis B Life Cycle: From Capsid Nuclear Import to cccDNA Formation

Dias

Sarica

Neuveut

2021

Viruses

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Hepatitis B virus (HBV) remains a major public health concern, with more than 250 million chronically infected people who are at high risk of developing liver diseases, including cirrhosis and hepatocellular carcinoma. Although antiviral treatments efficiently control virus replication and improve liver function, they cannot cure HBV infection. Viral persistence is due to the maintenance of the viral circular episomal DNA, called covalently closed circular DNA (cccDNA), in the nuclei of infected cells. cccDNA not only resists antiviral therapies, but also escapes innate antiviral surveillance. This viral DNA intermediate plays a central role in HBV replication, as cccDNA is the template for the transcription of all viral RNAs, including pregenomic RNA (pgRNA), which in turn feeds the formation of cccDNA through a step of reverse transcription. The establishment and/or expression of cccDNA is thus a prime target for the eradication of HBV. In this review, we provide an update on the current knowledge on the initial steps of HBV infection, from the nuclear import of the nucleocapsid to the formation of the cccDNA.

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The chaperone dynein LL1 mediates cytoplasmic transport of empty and mature hepatitis B virus capsids

Cited by 25 publications

References 46 publications

In Silico Discovery of Candidate Drugs against Covid-19

In Silico Discovery of Candidate Drugs against Covid-19

The established and the predicted roles of dynein light chain in the regulation of mitochondrial apoptosis

Early Steps of Hepatitis B Life Cycle: From Capsid Nuclear Import to cccDNA Formation

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