AIM2-Like Receptors Positively and Negatively Regulate the Interferon Response Induced by Cytosolic DNA

Nakaya, Yuki; Lilue, Jingtao; Stavrou, Spyridon; Moran, Eileen; Ross, Susan R.

doi:10.1128/mbio.00944-17

Cited by 57 publications

(66 citation statements)

References 65 publications

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“…In MEFs derived from TREX1knockout (KO) mice, interferon induction is dependent on cGAS (11,12), a recently discovered principal sensor of cytosolic DNA (13). Furthermore, Nakaya et al (14) reported that the Aim2 like receptors (ALRs) Aim2 and Ifi205 participated in both positive and negative regulation of the IFN/cytokine response to mouse retroelement DNAs that accumulated in TREX-deficient cells. Human loss-of-function mutations in TREX1 can cause autoimmune and autoinflammatory disorders, including Aicardi-Goutieres syndrome (AGS), which has features that mimic congenital viral infection and systemic lupus erythematosus (SLE) (12,15,16).…”

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confidence: 99%

HIV-1 Activation of Innate Immunity Depends Strongly on the Intracellular Level of TREX1 and Sensing of Incomplete Reverse Transcription Products

Kumar

Morrison

Dingli

et al. 2018

J Virol

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TREX1 has been reported to degrade cytosolic immune-stimulatory DNA, including viral DNA generated during HIV-1 infection; but the dynamic range of its capacity to suppress innate immune stimulation is unknown, and its full role in the viral life cycle remains unclear. A main purpose of our study was to determine how the intracellular level of TREX1 affects HIV-1 activation and avoidance of innate immunity. Using stable overexpression and CRISPR-mediated gene disruption, we engineered a range of TREX1 levels in human THP-1 monocytes. Increasing the level of TREX1 dramatically suppressed HIV-1 induction of interferon-stimulated genes (ISGs). Productive infection and integrated proviruses were equal or increased. Knocking out TREX1 impaired viral infectivity, increased early viral cDNA, and caused 10-fold or greater increases in HIV-1 ISG induction. Knockout of cyclic GMP-AMP synthase (cGAS) abrogated all ISG induction. Moreover, cGAS knockout produced no increase in single-cycle infection, establishing that HIV-1 DNA-triggered signaling is not rapid enough to impair the initial ISG-triggering infection cycle. Disruption of the HIV-1 capsid by PF74 also induced ISGs, and this was TREX1 level dependent, required reverse transcriptase catalysis, and was eliminated by cGAS gene knockout. Thus, the intracellular level of TREX1 pivotally modulates innate immune induction by HIV-1. Partial HIV-1 genomes are the TREX1 target and are sensed by cGAS. The nearly complete lack of innate immune induction despite equal or increased viral integration observed when the TREX1 protein level is experimentally elevated indicates that integration-competent genomes are shielded from cytosolic sensor-effectors during uncoating and transit to the nucleus. Much remains unknown about how TREX1 influences HIV-1 replication: whether it targets full-length viral DNA versus partial intermediates, how intracellular TREX1 protein levels correlate with ISG induction, and whether TREX1 digestion of cytoplasmic DNA and subsequent cGAS pathway activation affects both initial and subsequent cycles of infection. To answer these questions, we experimentally varied the intracellular level of TREX1 and showed that this strongly determines the innate immunogenicity of HIV-1. In addition, several lines of evidence, including time-of-addition experiments with drugs that impair reverse transcription or capsid integrity, showed that the pathogen-associated molecular patterns sensed after viral entry contain DNA, are TREX1 and cGAS substrates, and are derived from incomplete reverse transcriptase (RT) products. In contrast, the experiments demonstrate that full-length integration-competent viral DNA is immune to TREX1. Treatment approaches that reduce TREX1 levels or facilitate release of DNA intermediates may advantageously combine enhanced innate immunity with antiviral effects.

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confidence: 99%

HIV-1 Activation of Innate Immunity Depends Strongly on the Intracellular Level of TREX1 and Sensing of Incomplete Reverse Transcription Products

Kumar

Morrison

Dingli

et al. 2018

J Virol

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“…The phenotype of mice deficient of all 13 AIM2‐like PYHIN proteins indicated that p202 might not be absolutely required for DNA‐induced type I IFN production . However, currently we could not exclude the possibility that the lack of influence on DNA‐induced IFN expression in these mutant mice might be attributed to simultaneous deletion of multiple positive and negative regulators . In addition to AIM2 and IFI16‐α, whether IFI16‐β might interact with other human PYHIN proteins IFIX and MNDA to modulate their activity merits further analysis.…”

Section: Discussionmentioning

confidence: 94%

Inhibition of AIM 2 inflammasome activation by a novel transcript isoform of IFI 16

Wang

Deng

et al. 2018

EMBO Reports

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Mouse p202 is a disease locus for lupus and a dominant-negative inhibitor of AIM2 inflammasome activation. A human homolog of p202 has not been identified so far. Here, we report a novel transcript isoform of human IFI16-designated IFI16-β, which has a domain architecture similar to that of mouse p202. Like p202, IFI16-β contains two HIN domains, but lacks the pyrin domain. IFI16-β is ubiquitously expressed in various human tissues and cells. Its mRNA levels are also elevated in leukocytes of patients with lupus, virus-infected cells, and cells treated with interferon-β or phorbol ester. IFI16-β co-localizes with AIM2 in the cytoplasm, whereas IFI16-α is predominantly found in the nucleus. IFI16-β interacts with AIM2 to impede the formation of a functional AIM2-ASC complex. In addition, IFI16-β sequesters cytoplasmic dsDNA and renders it unavailable for AIM2 sensing. Enforced expression of IFI16-β inhibits the activation of AIM2 inflammasome, whereas knockdown of IFI16-β augments interleukin-1β secretion triggered by dsDNA but not dsRNA Thus, cytoplasm-localized IFI16-β is functionally equivalent to mouse p202 that exerts an inhibitory effect on AIM2 inflammasome.

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“…Our data are consistent with a requirement for both DDX41 and cGAS, the former perhaps in complex with IFI203, to achieve the full antiviral IFN response to retroviral reverse transcripts not protected by capsid or blocked by APOBEC3 proteins. Whether DDX41 requires interaction with IFI203 to achieve maximum effect in vivo will also be important to determine; however, Ifi203 shares a high degree of identity in the noncoding as well as coding regions with several other genes in the ALR locus, making a gene-specific knockout difficult to achieve (51). How nucleic acid-bound DDX41 activates STING is also not yet understood, although the two molecules are known to directly bind each other (9, 13)…”

Section: Discussionmentioning

confidence: 99%

DDX41 recognizes RNA/DNA retroviral reverse transcripts and is critical forin vivocontrol of MLV infection

Stavrou

Aguilera

Blouch

et al. 2018

Preprint

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1Host recognition of viral nucleic acids generated during infection leads to the activation 2 of innate immune responses essential for early control of virus. Retrovirus reverse transcription 3 creates numerous potential ligands for cytosolic host sensors that recognize foreign nucleic acids, 4 including single-stranded RNA (ssRNA), RNA/DNA hybrids and double stranded DNA (dsDNA). We 5 and others recently showed that the sensors cyclic GMP-AMP synthase (cGAS), dead-box helicase 6 41 (DDX41) and members of the Aim2-like receptor (ALR) family participate in the recognition of 7 retroviral reverse transcripts. However, why multiple sensors might be required and their relative 8 importance in in vivo control of retroviral infection is not known. Here we show that DDX41 9 primarily senses the DNA/RNA hybrid generated at the first step of reverse transcription, while 10 cGAS recognizes dsDNA generated at the next step. We also show that both DDX41 and cGAS are 11 needed for the anti-retroviral innate immune response to MLV and HIV in primary mouse 12 macrophages and dendritic cells (DC). Using mice with macrophage-or -specific knockout of the 13 DDX41 gene, we show that DDX41 sensing in DCs but not macrophages was critical for controlling 14 in vivo MLV infection. This suggests that DCs are essential in vivo targets for infection, as well as 15 for initiating the antiviral response. Our work demonstrates that the innate immune response to 16 retrovirus infection depends on multiple host nucleic acid sensors that recognize different 17 reverse transcription intermediates. 18 19 Importance 20 Viruses are detected by many different host sensors of nucleic acid, which in turn trigger 21 innate immune responses, such as type I IFN production, required to control infection. We show 22 Stavrou et al., 2017 3 here that at least two sensors are needed to initiate a highly effective innate immune response 23 to retroviruses -DDX41, which preferentially senses the RNA/DNA hybrid generated at the first 24 step of retrovirus replication and cGAS, which recognizes double-stranded DNA generated at the 25 2 nd step. Importantly, we demonstrate using mice lacking DDX41 or cGAS, that both sensors are 26 needed for the full antiviral response needed to control in vivo MLV infection. These findings 27 underscore the need for multiple host factors to counteract retroviral infection. 28 29 Stavrou et al.

show abstract

AIM2-Like Receptors Positively and Negatively Regulate the Interferon Response Induced by Cytosolic DNA

Cited by 57 publications

References 65 publications

HIV-1 Activation of Innate Immunity Depends Strongly on the Intracellular Level of TREX1 and Sensing of Incomplete Reverse Transcription Products

HIV-1 Activation of Innate Immunity Depends Strongly on the Intracellular Level of TREX1 and Sensing of Incomplete Reverse Transcription Products

Inhibition of AIM 2 inflammasome activation by a novel transcript isoform of IFI 16

DDX41 recognizes RNA/DNA retroviral reverse transcripts and is critical forin vivocontrol of MLV infection

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