A Balancing Act: MDA5 in Antiviral Immunity and Autoinflammation

Dias, Antônio Gregorio; Sampaio, Natália G.; Rehwinkel, Jan

doi:10.1016/j.tim.2018.08.007

Cited by 200 publications

(168 citation statements)

References 118 publications

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“…Limiting the gap between the 2 duplicated sequences to 2000 bp does not change the results, qualitatively (Additional file 2: Figure S1). This is consistent with the notion of avoidance of innate immunity activation by endogenous RNA, as viral dsRNA sensors are active in the cytoplasm [25]. Note, however, that stronger depletion of dsRNAs in pre-mRNAs is observed in a few species.…”

Section: Resultssupporting

confidence: 89%

Purifying selection of long dsRNA is the first line of defense against false activation of innate immunity

et al. 2020

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Background: Mobile elements comprise a large fraction of metazoan genomes. Accumulation of mobile elements is bound to produce multiple putative double-stranded RNA (dsRNA) structures within the transcriptome. These endogenous dsRNA structures resemble viral RNA and may trigger false activation of the innate immune response, leading to severe damage to the host cell. Adenosine to inosine (A-to-I) RNA editing is a common posttranscriptional modification, abundant within repetitive elements of all metazoans. It was recently shown that a key function of A-to-I RNA editing by ADAR1 is to suppress the immunogenic response by endogenous dsRNAs.Results: Here, we analyze the transcriptomes of dozens of species across the Metazoa and identify a strong genomic selection against endogenous dsRNAs, resulting in their purification from the canonical transcriptome. This purifying selection is especially strong for long and nearly perfect dsRNAs. These are almost absent from mRNAs, but not pre-mRNAs, supporting the notion of selection due to cytoplasmic processes. The few long and nearly perfect structures found in human transcripts are weakly expressed and often heavily edited. Conclusion: Purifying selection of long dsRNA is an important defense mechanism against false activation of innate immunity. This newly identified principle governs the integration of mobile elements into the genome, a major driving force of genome evolution. Furthermore, we find that most ADAR1 activity is not required to prevent an immune response to endogenous dsRNAs. The critical targets of ADAR1 editing are, likely, to be found mostly in non-canonical transcripts.

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Section: Resultssupporting

confidence: 89%

Purifying selection of long dsRNA is the first line of defense against false activation of innate immunity

et al. 2020

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“…is activated during virus infection is less well understood and is only briefly described here in light of a recent review on the subject 63 . Infection with many different types of virus, including RNA viruses and DNA viruses, results in the triggering of MDA5 signalling.…”

Section: Activation Of Mda5 During Viral Infection How Mda5mentioning

confidence: 99%

“…MDA5 is essential for type I interferon induction during infection with picornaviruses 16,17 , a family of positive-sense RNA viruses. For many other viruses, MDA5 appears either partially redundant with other sensors of infection or acts in a temporally distinct manner 63 . In many instances, infection with viruses that activate MDA5 results in the accumulation of dsRNA in the infected cell, which has been proposed to activate MDA5.…”

Section: Activation Of Mda5 During Viral Infection How Mda5mentioning

confidence: 99%

RIG-I-like receptors: their regulation and roles in RNA sensing

2020

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| Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are key sensors of virus infection, mediating the transcriptional induction of type I interferons and other genes that collectively establish an antiviral host response. Recent studies have revealed that both viral and host-derived RNAs can trigger RLR activation; this can lead to an effective antiviral response but also immunopathology if RLR activities are uncontrolled. In this Review , we discuss recent advances in our understanding of the types of RNA sensed by RLRs in the contexts of viral infection, malignancies and autoimmune diseases. We further describe how the activity of RLRs is controlled by host regulatory mechanisms, including RLR-interacting proteins, post-translational modifications and non-coding RNAs. Finally , we discuss key outstanding questions in the RLR field, including how our knowledge of RLR biology could be translated into new therapeutics.

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“…For example, the earliest up-regulated module, M_UP_1, incudes sensors of peptide and lipopeptide immune activators (TLR1, TLR2), whereas the subsequently up-regulated module, M_UP2, includes sensors of lipid immune activators (TREM2, SCARB2) together with receptors for viral nucleotides (TLR7, TLR9, Ifih1) that can also be activated by damaged or dysregulated endogenous DNA 12,[42][43][44][45][46] . Therefore, our microglial time-course analysis shows a prominence of DNA and RNA detecting immune receptors within the second phase of up-regulated MNMs, suggesting that nucleic acids activate inflammatory pathways as neuronal injury and disease progress ( Fig.…”

Section: Pathway Analysis To Expand Biological Insights Into Microglimentioning

confidence: 99%

“…Furthermore, at the center of the anti-inflammasome module PPI map is MDA5 (Ifih1), a receptor of dsRNA that can activate type 1 interferon response downstream of viral detection or chromatin destabilization 44,45,53 (Fig. 4B).…”

Section: Identification Of the Inflammasome And Anti-inflammasome Relmentioning

confidence: 99%

Dementia risk genes engage gene networks poised to tune the immune response towards chronic inflammatory states

Rexach

Swarup

Chang

et al. 2019

Preprint

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An emerging challenge in neurodegenerative dementia is understanding how immune-associated genes and pathways contribute to disease. To achieve a refined view of neuroinflammatory signaling across neurodegeneration, we took an integrative functional genomics approach to consider neurodegeneration from the perspective of microglia and their interactions with other cells. Using large-scale gene expression and perturbation data, regulatory motif analysis, and gene knockout studies, we identify and characterize a microglial-centric network involving distinct gene co-expression modules associated with progressive stages of neurodegeneration. These modules, which are conserved from mouse to human, differentially incorporate specific immune sensors of cellular damage and pathways that are predicted to eventually tune the immune response toward chronic inflammation and immune suppression. Notably, common genetic risk for Alzheimer's disease (AD), Frontotemporal dementia (FTD) and Progressive Supranuclear Palsy (PSP) resides in specific modules that distinguish between the disorders, but also show convergence on pathways related to anti-viral defense mechanisms. These results suggest a model wherein combinatorial microglial-immune signaling integrate specific immune activators and disease genes that lead to the establishment of chronic states of simultaneous inflammation and immunosuppression involving type 1 interferon in these dementias.

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A Balancing Act: MDA5 in Antiviral Immunity and Autoinflammation

Cited by 200 publications

References 118 publications

Purifying selection of long dsRNA is the first line of defense against false activation of innate immunity

Purifying selection of long dsRNA is the first line of defense against false activation of innate immunity

RIG-I-like receptors: their regulation and roles in RNA sensing

Dementia risk genes engage gene networks poised to tune the immune response towards chronic inflammatory states

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