DNA damage and innate immunity: links and trade-offs

Chatzinikolaou, Georgia; Karakasilioti, Ismene; Garinis, George A.

doi:10.1016/j.it.2014.06.003

Cited by 126 publications

(103 citation statements)

References 89 publications

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“…These findings raise the possibility that rare infected cells or HBc mutations, leading to enhanced RC DNA exposure, may arise as the infection proceeds, thus contributing to the induction of innate immunity by triggering the host DNAsensing mechanism. Furthermore, the peculiar structure of the HBV RC DNA, a "broken" molecule, may render it particularly potent at triggering the cellular DNA sensors, given the connection between DNA damage and innate DNA sensing (58). Reports of at least some innate immune responses during natural or experimental HBV infections lend support to this suggestion (19,(59)(60)(61).…”

Section: Discussionmentioning

confidence: 99%

Viral DNA-Dependent Induction of Innate Immune Response to Hepatitis B Virus in Immortalized Mouse Hepatocytes

Cui

Clark

Liu

et al. 2016

J Virol

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Hepatitis B virus (HBV) infects hundreds of millions of people worldwide and causes acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma. HBV is an enveloped virus with a relaxed circular (RC) DNA genome. In the nuclei of infected human hepatocytes, conversion of RC DNA from the incoming virion or cytoplasmic mature nucleocapsid (NC) to the covalently closed circular (CCC) DNA, which serves as the template for producing all viral transcripts, is essential to establish and sustain viral replication. A prerequisite for CCC DNA formation is the uncoating (disassembly) of NCs to expose their RC DNA content for conversion to CCC DNA. We report here that in an immortalized mouse hepatocyte cell line, AML12HBV10, in which RC DNA exposure is enhanced, the exposed viral DNA could trigger an innate immune response that was able to modulate viral gene expression and replication. When viral gene expression and replication were low, the innate response initially stimulated these processes but subsequently acted to shut off viral gene expression and replication after they reached peak levels. Inhibition of viral DNA synthesis or cellular DNA sensing and innate immune signaling diminished the innate response. These results indicate that HBV DNA, when exposed in the host cell cytoplasm, can function to trigger an innate immune response that, in turn, modulates viral gene expression and replication. IMPORTANCE Chronic infection by hepatitis B virus (HBV) afflicts hundreds of millions worldwide and is sustained by the episomal covalently closed circular (CCC) DNA in the nuclei of infected hepatocytes.Release of viral genomic DNA from cytoplasmic nucleocapsids (NCs) (NC disassembly or uncoating) is a prerequisite for its conversion to CCC DNA, which can also potentially expose the viral DNA to host DNA sensors and trigger an innate immune response. We have found that in an immortalized mouse hepatocyte cell line in which efficient CCC DNA formation was associated with enhanced exposure of nucleocapsid-associated DNA, the exposed viral DNA indeed triggered host cytoplasmic DNA sensing and an innate immune response that was able to modulate HBV gene expression and replication. Thus, HBV can, under select conditions, be recognized by the host innate immune response through exposed viral DNA, which may be exploited therapeutically to clear viral persistence. Hepatitis B virus (HBV) has infected approximately 2 billion people worldwide, with 350 million of them becoming chronically infected (1). Annually, 1 million fatalities are attributed to acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) caused by HBV. HBV is a small, enveloped DNA virus that contains a 3.2-kb, partially double-stranded (DS), relaxed circular (RC) DNA genome and replicates via an RNA intermediate, the pregenomic RNA (pgRNA). Upon infection, HBV RC DNA is converted to covalently closed circular (CCC) DNA in the nuclei of infected human hepatocytes, which serves as the transcriptional template for all viral RNAs, incl...

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Section: Discussionmentioning

confidence: 99%

Viral DNA-Dependent Induction of Innate Immune Response to Hepatitis B Virus in Immortalized Mouse Hepatocytes

Cui

Clark

Liu

et al. 2016

J Virol

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“…Although there is no known linkage between SAMHD1 and the SLX4 complex, it is interesting that, in addition to the type 1 interferonopathy Aicardi Goutières syndrome, SAMHD1 mutations are also found in chronic lymphocytic leukemias and that SAMHD1 itself is recruited to DNA damage foci (42). Thus, there is plenty of scope for convergence of pathways involving DNA damage sensing, repair processes, and the ability of the cell to defend itself against DNA-based pathogens in the nucleus (43). Study of Vpr/ SLX4 interactions will therefore yield further insight into the regulation of these pathways.…”

Section: Discussionmentioning

confidence: 99%

G ₂ /M Cell Cycle Arrest Correlates with Primate Lentiviral Vpr Interaction with the SLX4 Complex

Berger

Lawrence

Hué

et al. 2015

J Virol

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V iral protein R (Vpr) is an accessory protein common to all primate lentiviruses whose role in viral replication remains unclear. It is packaged specifically into virions and is associated with the reverse-transcription complex during early steps of infection (1, 2). Although implicated in various virological processes, the major phenotype ascribed to Vpr is the induction of G 2 /M cell cycle arrest in dividing cells (3, 4). The importance of this phenotype in human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) replication has been notoriously difficult to define because of the minor effects of its deletion on viral replication in cell culture (5). However, reversion of inactivating mutations in both primates and humans highlights that Vpr plays an essential role for viral replication in vivo (6). In addition to cell cycle arrest, several SIV Vpr alleles are capable of targeting the host restriction factor SAMHD1 and that function became separated in the sooty mangabey SIV (SIVsm) lineage upon duplication to generate the vpx gene peculiar to this group (7). Importantly, at present HIV-1 Vpr is not known to retain any SAMHD1 counteractivity (7-10).Vpr-mediated cell cycle arrest depends on its localization to nuclear compartments and the ability to hijack a Cullin-4/DDB1/ Roc1 E3 ubiquitin ligase complex through the WD-containing DCAF-1 adaptor (11,12). For HIV-1 Vpr, this leads ultimately to the activation of the ataxia telangiectasia M and Rad3-related (ATR) and Chk1 kinases to prevent cell cycle progression into mitosis (13). Although several putative Vpr targets have been described, the identity of that which triggers this event has until recently remained elusive. The requirement for the ubiquitin-proteasome system and, in particular, K48-ubiquitin linkages supported a notion that the Vpr target is degraded (14). However, Laguette and colleagues recently found that Vpr interacts with the SLX4 complex, members of the Fanconi anemia DNA repair pathway (15). SLX4, also known as Fanconi anemia complementation group P (FANCP), is a large adaptor protein that acts as a scaffold for a heterodimeric structure-specific endonuclease comprised of MUS81 and EME1. This interaction directs this endonuclease and

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“…Some of the DNA repair factors have been shown to localize in mitochondria. Furthermore, immune system has been suggested to be under the regulation of DNA repair [14]. Therefore, understanding the co-operation of the telomeremitochondria-DNA repair-immune response might contribute to reveal molecular mechanism of cellular senescence, cancer and immunological diseases.…”

Section: Relationships Between Dna-repair Mitochondrial Functions Anmentioning

confidence: 99%

Transcriptional Regulation of the Human Genes that Encode DNA Repair- and Mitochondrial Function-Associated Proteins

Uchiumi¹,

Larsen²,

Tanuma³

2015

Advances in DNA Repair

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DNA damage and innate immunity: links and trade-offs

Cited by 126 publications

References 89 publications

Viral DNA-Dependent Induction of Innate Immune Response to Hepatitis B Virus in Immortalized Mouse Hepatocytes

Viral DNA-Dependent Induction of Innate Immune Response to Hepatitis B Virus in Immortalized Mouse Hepatocytes

G ₂ /M Cell Cycle Arrest Correlates with Primate Lentiviral Vpr Interaction with the SLX4 Complex

Transcriptional Regulation of the Human Genes that Encode DNA Repair- and Mitochondrial Function-Associated Proteins

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DNA damage and innate immunity: links and trade-offs

Cited by 126 publications

References 89 publications

Viral DNA-Dependent Induction of Innate Immune Response to Hepatitis B Virus in Immortalized Mouse Hepatocytes

Viral DNA-Dependent Induction of Innate Immune Response to Hepatitis B Virus in Immortalized Mouse Hepatocytes

G 2 /M Cell Cycle Arrest Correlates with Primate Lentiviral Vpr Interaction with the SLX4 Complex

Transcriptional Regulation of the Human Genes that Encode DNA Repair- and Mitochondrial Function-Associated Proteins

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Product

Resources

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G ₂ /M Cell Cycle Arrest Correlates with Primate Lentiviral Vpr Interaction with the SLX4 Complex