scholarly journals The innate immune DNA sensor cGAS is a negative regulator of DNA repair hence promotes genome instability and cell death

2018 ◽  
Author(s):  
Hui Jiang ◽  
Swarupa Panda ◽  
Xiaoyu Xue ◽  
Fengshan Liang ◽  
Patrick Sung ◽  
...  
Keyword(s):  
Dna Repair ◽  
Genome Instability ◽  
Inflammatory Diseases ◽  
Innate Immune ◽  
Negative Regulator ◽  
Dna Sensor ◽  
Innate Immune Signaling ◽  
Mitotic Death ◽  
Strand Invasion ◽  
Dna Strand

ABSTRACTStringent regulation of DNA repair is essential for organismal integrity, but the mechanisms are not fully understood. Cyclic cGMP-AMP synthase (cGAS), the DNA sensor that alerts the innate immune system to the presence of foreign or damaged self-DNA in the cytoplasm is critical for the outcome of infections, inflammatory diseases and cancer. Besides this cytoplasmic function as an innate immune sensor, whether cGAS fulfills other biological roles remains unknown. Here we report that cGAS has a distinct role in the nucleus: it inhibits homologous recombination DNA repair (HR) thereby promoting genome instability and associated micronuclear generation and mitotic death. We show that cGAS-mediated inhibition of HR requires its DNA binding and oligomerization but not its catalytic activity or the downstream innate immune signaling events. Mechanistically, we show that cGAS impede RAD51-mediated DNA strand invasion, a key step in HR. These results uncover a new function of cGAS relevant for understanding its involvement in genome instability- associated disorders.

scholarly journals NLRC3, a Member of the NLR Family of Proteins, Is a Negative Regulator of Innate Immune Signaling Induced by the DNA Sensor STING

Immunity ◽  
2014 ◽  
Vol 40 (3) ◽  
pp. 329-341 ◽  
Author(s):  
Lu Zhang ◽  
Jinyao Mo ◽  
Karen V. Swanson ◽  
Haitao Wen ◽  
Alex Petrucelli ◽  
...  
Keyword(s):  
Innate Immune ◽  
Negative Regulator ◽  
Dna Sensor ◽  
Immune Signaling ◽  
Innate Immune Signaling

The innate immune DNA sensor cGAS: A membrane, cytosolic, or nuclear protein?

2019 ◽  
Vol 12 (581) ◽  
pp. eaax3521 ◽  
Author(s):  
Nelson O. Gekara ◽  
Hui Jiang
Keyword(s):  
Immune System ◽  
Subcellular Localization ◽  
Innate Immune System ◽  
Nuclear Protein ◽  
Inflammatory Diseases ◽  
Innate Immune ◽  
Dna Sensor ◽  
Terminal Domain

Cyclic cGMP-AMP synthase (cGAS) alerts the innate immune system to the presence of foreign or damaged self-DNA inside the cell and is critical for the outcome of infections, inflammatory diseases, and cancer. Two studies now demonstrate that cGAS activation is regulated by differential subcellular localization through its non-enzymatic, N-terminal domain.

scholarly journals PSMB1 Negatively Regulates the Innate Antiviral Immunity by Facilitating Degradation of IKK-ε

Viruses ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 99
Author(s):  
Fangyi Wu ◽  
Zhenmin Niu ◽  
Bin Zhou ◽  
Pengcheng Li ◽  
Feng Qian
Keyword(s):  
Viral Infection ◽  
Rna Virus ◽  
Cell Cycle Control ◽  
Ubiquitin Proteasome System ◽  
Innate Immune ◽  
Negative Regulator ◽  
Viral Immunity ◽  
Chemokine Production ◽  
Cellular Processes ◽  
Innate Immune Signaling

Proteasome is a large protein complex, which degrades most intracellular proteins. It regulates numerous cellular processes, including the removal of misfolded or unfolded proteins, cell cycle control, and regulation of apoptosis. However, the function of proteasome subunits in viral immunity has not been well characterized. In this study, we identified PSMB1, a member of the proteasome β subunits (PSMB) family, as a negative regulator of innate immune responses during viral infection. Knockdown of PSMB1 enhanced the RNA virus-induced cytokine and chemokine production. Overexpression of PSMB1 abolished virus-induced activation of the interferon-stimulated response element (ISRE) and interferon beta (IFNβ) promoters. Mechanistically, PSMB1 inhibited the activation of RIG-I-like receptor (RLR) and Toll-like receptor 3 (TLR3) signaling pathways. PSMB1 was induced after viral infection and its interaction with IKK-ε promoted degradation of IKK-ε through the ubiquitin-proteasome system. Collectively, our study demonstrates PSMB1 is an important regulator of innate immune signaling.

Links Between Defective DNA Strand Break Repair and Genome Instability in Fanconi Anemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. SCI-2-SCI-2
Author(s):  
Stephen C. West
Keyword(s):  
Dna Repair ◽  
Fanconi Anemia ◽  
Conflicts Of Interest ◽  
Genome Instability ◽  
Strand Break ◽  
Breast Cancers ◽  
Recombination Proteins ◽  
Living Organisms ◽  
Dna Strand ◽  
Key Events

Abstract Abstract SCI-2 All living organisms feature DNA repair pathways that safeguard the integrity of the genome, and mutations in proteins that mediate key events in DNA repair have been linked to genome instability and tumorigenesis. Homologous recombination provides an important DNA repair pathway that is needed for the restoration and restart of broken replication forks, for the rejoining of chromosome/chromatid breaks, and for the processing of DNA cross-links. Mutations in genes that encode a variety of recombination proteins are linked to breast cancers and to heritable diseases such as Bloom syndrome (BS) and Fanconi anemia (FA). In recent work, we purified the BLM protein (defective in BS), the BRCA2 (FANCND1) and PALB2 (FANCN) tumor suppressors (mutated in some cases of FA), and the newly discovered FANCP protein, also known as SLX4, and have initiated structure-function analyses to elucidate their molecular functions. How these proteins process DNA, and how they are regulated and controlled to direct the outcome of recombinational repair is now revealing unexpected insights that extend our understanding of efficient DNA repair and tumor avoidance. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Interleukin-37 regulates innate immune signaling in human and mouse colonic organoids

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Joannie M. Allaire ◽  
Anita Poon ◽  
Shauna M. Crowley ◽  
Xiao Han ◽  
Zohreh Sharafian ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Individual Variability ◽  
Innate Immune ◽  
Negative Regulator ◽  
Intestinal Epithelial ◽  
Immune Signaling ◽  
Strong Expression ◽  
Innate Immune Signaling ◽  
Close Proximity ◽  
Species Specific

AbstractIntestinal epithelial cells (IEC) reside in close proximity to the gut microbiota and are hypo-responsive to bacterial products, likely to prevent maladaptive inflammatory responses. This is in part due to their strong expression of Single Ig IL-1 related receptor (SIGIRR), a negative regulator of interleukin (IL)-1 and toll-like receptor signaling. IL-37 is an anti-inflammatory cytokine that inhibits innate signaling in diverse cells by signaling through SIGIRR. Despite the strong expression of SIGIRR by IEC, few studies have examined whether IL-37 can suppress their innate immune signaling. We characterized innate immune responses of human and murine colonoids to bacteria (FliC, LPS) and host (IL-1β) products and the role of IL-37/SIGIRR in regulating these responses. We demonstrated that human colonoids responded only to FliC, but not to LPS or IL-1β. While colonoids derived from different donors displayed significant inter-individual variability in the magnitude of their innate responses to FliC stimulation, all colonoids released a variety of chemokines. Interestingly, IL-37 attenuated these responses through inhibition of p38 and NFκB signaling pathways. We determined that this suppression by IL-37 was SIGIRR dependent, in murine organoids. Along with species-specific differences in IEC innate responses, we show that IL-37 can promote IEC hypo-responsiveness by suppressing inflammatory signaling.

scholarly journals Interleukin-37 Regulates Innate Immune Signaling in Human and Mouse Colonic Organoids

2020 ◽  
Author(s):  
Joannie Allaire ◽  
Anita Poon ◽  
Shauna Crowley ◽  
Xiao Han ◽  
Navjit Moore ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Individual Variability ◽  
Innate Immune ◽  
Negative Regulator ◽  
Intestinal Epithelial ◽  
Immune Signaling ◽  
Strong Expression ◽  
Innate Immune Signaling ◽  
Close Proximity ◽  
Species Specific

Abstract Intestinal epithelial cells (IEC) reside in close proximity to the gut microbiota and are hypo-responsive to bacterial products, likely to prevent maladaptive inflammatory responses. This is in part due to their strong expression of Single Ig IL-1 related receptor (SIGIRR), a negative regulator of interleukin (IL)-1 and toll-like receptor signaling. IL-37, an anti-inflammatory cytokine that inhibits innate signaling in diverse cells by signaling through SIGIRR. Despite the strong expression of SIGIRR by IEC, few studies have examined whether IL-37 can suppress their innate immune signaling. We characterized innate immune responses of human and murine colonoids to bacteria (FliC, LPS) and host (IL-1β) products and the role of IL-37/SIGIRR in regulating these responses. We demonstrated that human colonoids responded only to FliC, but not to LPS or IL-1β. While colonoids derived from different donors displayed significant inter-individual variability in the magnitude of their innate responses to FliC stimulation, all colonoids released a variety of chemokines. Interestingly, IL-37 attenuated these responses through inhibition of p38 and NFκB signaling pathways. We determined that this suppression by IL-37 was SIGIRR dependent, in murine organoids. Along with species-specific differences in IEC innate responses, we show that IL-37 can promote IEC hypo-responsiveness by supressing inflammatory signaling.

scholarly journals PPM1G restricts innate immune signaling mediated by STING and MAVS and is hijacked by KSHV for immune evasion

2020 ◽  
Vol 6 (47) ◽  
pp. eabd0276
Author(s):  
Kuai Yu ◽  
Huabin Tian ◽  
Hongyu Deng
Keyword(s):  
Immune Evasion ◽  
Adaptor Proteins ◽  
Antiviral Response ◽  
Innate Immune ◽  
Negative Regulator ◽  
Host Protein ◽  
Type I ◽  
Dna And Rna ◽  
Innate Immune Signaling ◽  
Interferon Pathway

The adaptor proteins, STING and MAVS, are components of critical pathogen-sensing pathways that induce innate immunity. Phosphorylation of either adaptor results in activation of the type I interferon pathway. How this phosphorylation is regulated and how it is manipulated by pathogens remain largely unknown. Here, we identified host protein phosphatase, Mg2+/Mn2+ dependent 1G (PPM1G) as a negative regulator of innate immune pathways and showed that this host system is hijacked by Kaposi’s sarcoma-associated herpesvirus (KSHV). Mechanistically, KSHV tegument protein ORF33 interacts with STING/MAVS and enhances recruitment of PPM1G to dephosphorylate p-STING/p-MAVS for immunosuppression. Inhibition of PPM1G expression improves the antiviral response against both DNA and RNA viruses. Collectively, our study shows that PPM1G restricts both cytosolic DNA– and RNA–sensing pathways to naturally balance the intensity of the antiviral response. Manipulation of PPM1G by KSHV provides an important strategy for immune evasion.

scholarly journals IκB Kinase β Phosphorylates the K63 Deubiquitinase A20 To Cause Feedback Inhibition of the NF-κB Pathway

2007 ◽  
Vol 27 (21) ◽  
pp. 7451-7461 ◽  
Author(s):  
Jessica E. Hutti ◽  
Benjamin E. Turk ◽  
John M. Asara ◽  
Averil Ma ◽  
Lewis C. Cantley ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Feedback Inhibition ◽  
Innate Immune ◽  
Negative Regulator ◽  
Immune Signaling ◽  
Innate Immune Signaling ◽  
Iκb Kinase ◽  
Phosphorylation Event

ABSTRACT Misregulation of NF-κB signaling leads to infectious, inflammatory, or autoimmune disorders. IκB kinase β (IKKβ) is an essential activator of NF-κB and is known to phosphorylate the NF-κB inhibitor, IκBα, allowing it to undergo ubiquitin-mediated proteasomal degradation. However, beyond IκBα, few additional IKKβ substrates have been identified. Here we utilize a peptide library and bioinformatic approach to predict likely substrates of IKKβ. This approach predicted Ser381 of the K63 deubiquitinase A20 as a likely site of IKKβ phosphorylation. While A20 is a known negative regulator of innate immune signaling pathways, the mechanisms regulating the activity of A20 are poorly understood. We show that IKKβ phosphorylates A20 in vitro and in vivo at serine 381, and we further show that this phosphorylation event increases the ability of A20 to inhibit the NF-κB signaling pathway. Phosphorylation of A20 by IKKβ thus represents part of a novel feedback loop that regulates the duration of NF-κB signaling following activation of innate immune signaling pathways.

scholarly journals Spatiotemporal dynamics of innate immune signaling via RIG-I–like receptors

2020 ◽  
Vol 117 (27) ◽  
pp. 15778-15788 ◽  
Author(s):  
Katharina Esser-Nobis ◽  
Lauren D. Hatfield ◽  
Michael Gale
Keyword(s):  
Innate Immunity ◽  
Virus Infection ◽  
Rna Virus ◽  
Adaptor Protein ◽  
Innate Immune ◽  
Negative Regulator ◽  
Resting Cells ◽  
Immune Signaling ◽  
Innate Immune Signaling ◽  
Irf3 Activation

RIG-I, MDA5, and LGP2 comprise the RIG-I–like receptors (RLRs). RIG-I and MDA5 are essential pathogen recognition receptors sensing viral infections while LGP2 has been described as both RLR cofactor and negative regulator. After sensing and binding to viral RNA, including double-stranded RNA (dsRNA), RIG-I and MDA5 undergo cytosol-to-membrane relocalization to bind and signal through the MAVS adaptor protein on intracellular membranes, thus directing downstream activation of IRF3 and innate immunity. Here, we report examination of the dynamic subcellular localization of all three RLRs within the intracellular response to dsRNA and RNA virus infection. Observations from high resolution biochemical fractionation and electron microscopy, coupled with analysis of protein interactions and IRF3 activation, show that, in resting cells, microsome but not mitochondrial fractions harbor the central components to initiate innate immune signaling. LGP2 interacts with MAVS in microsomes, blocking the RIG-I/MAVS interaction. Remarkably, in response to dsRNA treatment or RNA virus infection, LGP2 is rapidly released from MAVS and redistributed to mitochondria, temporally correlating with IRF3 activation. We reveal that IRF3 activation does not take place on mitochondria but instead occurs at endoplasmic reticulum (ER)-derived membranes. Our observations suggest ER-derived membranes as key RLR signaling platforms controlled through inhibitory actions of LGP2 binding to MAVS wherein LGP2 translocation to mitochondria releases MAVS inhibition to facilitate RLR-mediated signaling of innate immunity.

scholarly journals A Link between Replicative Stress, Lamin Proteins, and Inflammation

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 552
Author(s):  
Simon Willaume ◽  
Emilie Rass ◽  
Paula Fontanilla-Ramirez ◽  
Angela Moussa ◽  
Paul Wanschoor ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Molecular Mechanisms ◽  
Genome Instability ◽  
Inflammatory Diseases ◽  
Dna Lesions ◽  
Inflammatory Factors ◽  
Replicative Stress ◽  
Damage Repair ◽  
Beneficial Response

Double-stranded breaks (DSB), the most toxic DNA lesions, are either a consequence of cellular metabolism, programmed as in during V(D)J recombination, or induced by anti-tumoral therapies or accidental genotoxic exposure. One origin of DSB sources is replicative stress, a major source of genome instability, especially when the integrity of the replication forks is not properly guaranteed. To complete stalled replication, restarting the fork requires complex molecular mechanisms, such as protection, remodeling, and processing. Recently, a link has been made between DNA damage accumulation and inflammation. Indeed, defects in DNA repair or in replication can lead to the release of DNA fragments in the cytosol. The recognition of this self-DNA by DNA sensors leads to the production of inflammatory factors. This beneficial response activating an innate immune response and destruction of cells bearing DNA damage may be considered as a novel part of DNA damage response. However, upon accumulation of DNA damage, a chronic inflammatory cellular microenvironment may lead to inflammatory pathologies, aging, and progression of tumor cells. Progress in understanding the molecular mechanisms of DNA damage repair, replication stress, and cytosolic DNA production would allow to propose new therapeutical strategies against cancer or inflammatory diseases associated with aging. In this review, we describe the mechanisms involved in DSB repair, the replicative stress management, and its consequences. We also focus on new emerging links between key components of the nuclear envelope, the lamins, and DNA repair, management of replicative stress, and inflammation.

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