Erratum to: Inhibition of the Innate Immune Receptors for Foreign DNA Sensing Improves Transfection Efficiency of Gene Electrotransfer in Melanoma B16F10 Cells

ABSTRACTThe cellular innate immune system recognizing pathogen infection is essential for host defense against viruses. In parallel, viruses have developed a variety of strategies to evade the innate immunity. The hepatitis B virus (HBV), a DNA virus that causes chronic hepatitis, has been shown to inhibit RNA helicase RIG-I-mediated interferon (IFN) induction. However, it is still unknown whether HBV could affect the host DNA-sensing pathways. Here we report that in transiently HBV-transfected Huh7 cells, the stably HBV-producing cell line HepAD38, and HBV-infected HepaRG cells and primary human hepatocytes, HBV markedly interfered with IFN-β induction and antiviral immunity mediated by the stimulator of interferon genes (STING), which has been identified as a central factor in foreign DNA recognition and antiviral innate immunity. Screening analysis demonstrated that the viral polymerase (Pol), but not other HBV-encoded proteins, was able to inhibit STING-stimulated interferon regulatory factor 3 (IRF3) activation and IFN-β induction. Moreover, the reverse transcriptase (RT) and the RNase H (RH) domains of Pol were identified to be responsible for the inhibitory effects. Furthermore, Pol was shown to physically associate with STING and dramatically decrease the K63-linked polyubiquitination of STING via its RT domain without altering the expression level of STING. Taken together, these observations suggest that besides its inherent catalytic function, Pol has a role in suppression of IFN-β production by direct interaction with STING and subsequent disruption of its K63-linked ubiquitination, providing a new mechanism for HBV to counteract the innate DNA-sensing pathways.IMPORTANCEAlthough whether and how HBV infection induces the innate immune responses are still controversial, it has become increasingly clear that HBV has developed strategies to counteract the pattern recognition receptor-mediated signaling pathways. Previous studies have shown that type I IFN induction activated by the host RNA sensors could be inhibited by HBV. However, it remains unknown whether HBV as a DNA virus utilizes evasion mechanisms against foreign DNA-elicited antiviral signaling. In recent years, the cytosolic DNA sensor and key adaptor STING has been demonstrated to be essential in multiple foreign DNA-elicited innate immune signalings. Here, for the first time, we report STING as a new target of HBV to antagonize IFN induction and identify the viral polymerase responsible for the inhibitory effect, thus providing an additional molecular mechanism by which HBV evades the innate immunity; this implies that in addition to its inherent catalytic function, HBV polymerase is a multifunctional immunomodulatory protein.

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Human DNA-PK activates a STING-independent DNA sensing pathway

10.1101/587501 ◽

2019 ◽

Author(s):

Katelyn Burleigh ◽

Joanna H. Maltbaek ◽

Stephanie Cambier ◽

Richard Green ◽

Michael Gale ◽

...

Keyword(s):

Kinase Activity ◽

Human Adenovirus ◽

Innate Immune ◽

Type I ◽

Dna Sensing ◽

Human Dna ◽

Foreign Dna ◽

Sting Pathway ◽

Viral Antagonists ◽

Adenovirus 5

SummaryDetection of intracellular DNA by the cGAS-STING pathway activates a type I interferon-mediated innate immune response that protects from virus infection and can be harnessed to promote anti-tumor immunity. Whether there are additional DNA sensing pathways, and how such pathways might function, remains controversial. We show here that humans – but not mice – have a second, potent, STING-independent DNA sensing pathway that is blocked by the E1A viral oncogene of human adenovirus 5. We identify human DNA-PK as the sensor of this pathway and demonstrate that DNA-PK kinase activity drives a robust and broad antiviral response. We discover that the heat shock protein HSPA8/HSC70 is a unique target of DNA-PK. Finally, we demonstrate that detection of foreign DNA and DNA damage trigger distinct modalities of DNA-PK activity. These findings reveal the existence, sensor, unique target, and viral antagonists of a STING-independent DNA sensing pathway (SIDSP) in human cells.

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Faculty Opinions recommendation of Inflammatory caspases are innate immune receptors for intracellular LPS.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718530133.793544987 ◽

2018 ◽

Author(s):

Jerrold Weiss

Keyword(s):

Innate Immune ◽

Immune Receptors ◽

Inflammatory Caspases

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Effects of innate immune receptor stimulation on extracellular α-synuclein uptake and degradation by brain resident cells

Experimental & Molecular Medicine ◽

10.1038/s12276-021-00562-6 ◽

2021 ◽

Author(s):

Changyoun Kim ◽

Somin Kwon ◽

Michiyo Iba ◽

Brian Spencer ◽

Edward Rockenstein ◽

...

Keyword(s):

Degradation Kinetics ◽

Morphological Changes ◽

Direct Interaction ◽

Innate Immune ◽

Pathological Feature ◽

Tlr2 Expression ◽

Immune Receptors ◽

Age Related ◽

Stimulation Of

AbstractSynucleinopathies are age-related neurological disorders characterized by the progressive deposition of α-synuclein (α-syn) aggregates and include Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Although cell-to-cell α-syn transmission is thought to play a key role in the spread of α-syn pathology, the detailed mechanism is still unknown. Neuroinflammation is another key pathological feature of synucleinopathies. Previous studies have identified several immune receptors that mediate neuroinflammation in synucleinopathies, such as Toll-like receptor 2 (TLR2). However, the species of α-syn aggregates varies from study to study, and how different α-syn aggregate species interact with innate immune receptors has yet to be addressed. Therefore, we investigated whether innate immune receptors can facilitate the uptake of different species of α-syn aggregates. Here, we examined whether stimulation of TLRs could modulate the cellular uptake and degradation of α-syn fibrils despite a lack of direct interaction. We observed that stimulation of TLR2 in vitro accelerated α-syn fibril uptake in neurons and glia while delaying the degradation of α-syn in neurons and astrocytes. Internalized α-syn was rapidly degraded in microglia regardless of whether TLR2 was stimulated. However, cellular α-syn uptake and degradation kinetics were not altered by TLR4 stimulation. In addition, upregulation of TLR2 expression in a synucleinopathy mouse model increased the density of Lewy-body-like inclusions and induced morphological changes in microglia. Together, these results suggest that cell type-specific modulation of TLR2 may be a multifaceted and promising therapeutic strategy for synucleinopathies; inhibition of neuronal and astroglial TLR2 decreases pathogenic α-syn transmission, but activation of microglial TLR2 enhances microglial extracellular α-syn clearance.

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Innate Immune DNA Sensing of Flaviviruses

Viruses ◽

10.3390/v12090979 ◽

2020 ◽

Vol 12 (9) ◽

pp. 979

Author(s):

Tongtong Zhu ◽

Ana Fernandez-Sesma

Keyword(s):

Innate Immune System ◽

Rna Viruses ◽

Innate Immune ◽

Host Factors ◽

Dna Sensing ◽

Antiviral Responses ◽

Sensory Pathways ◽

Sensing System ◽

Positive Sense ◽

Successful Replication

Flaviviruses are arthropod-borne RNA viruses that have been used extensively to study host antiviral responses. Often selected just to represent standard single-stranded positive-sense RNA viruses in early studies, the Flavivirus genus over time has taught us how truly unique it is in its remarkable ability to target not just the RNA sensory pathways but also the cytosolic DNA sensing system for its successful replication inside the host cell. This review summarizes the main developments on the unexpected antagonistic strategies utilized by different flaviviruses, with RNA genomes, against the host cyclic GAMP synthase (cGAS)/stimulator of interferon genes (STING) cytosolic DNA sensing pathway in mammalian systems. On the basis of the recent advancements on this topic, we hypothesize that the mechanisms of viral sensing and innate immunity are much more fluid than what we had anticipated, and both viral and host factors will continue to be found as important factors contributing to the host innate immune system in the future.

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