ALG2 regulates type I interferon responses by inhibiting STING trafficking

Stimulator of IFN genes (STING), an endoplasmic reticulum (ER) signaling adaptor, is essential for the type I interferon response to cytosolic dsDNA. The translocation from the ER to perinuclear vesicles following binding cGAMP is a critical step for STING to activate downstream signaling molecules, which lead to the production of interferon and pro-inflammatory cytokines. Here we found that apoptosis-linked gene 2 (ALG2) suppressed STING signaling induced by either HSV-1 infection or cGAMP presence. Knockout of ALG2 markedly facilitated the expression of type I interferons upon cGAMP treatment or HSV-1 infection in THP-1 monocytes. Mechanistically, ALG2 associated with the C-terminal tail (CTT) of STING and inhibited its trafficking from ER to perinuclear region. Furthermore, the ability of ALG2 to coordinate calcium was crucial for its regulation of STING trafficking and DNA-induced innate immune responses. This work suggests that ALG2 is involved in DNA-induced innate immune responses by regulating STING trafficking.

Download Full-text

Type-I interferon signatures in SARS-CoV-2 infected Huh7 cells

Cell Death Discovery ◽

10.1038/s41420-021-00487-z ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Xi Chen ◽

Elisa Saccon ◽

K. Sofia Appelberg ◽

Flora Mikaeloff ◽

Jimmy Esneider Rodriguez ◽

...

Keyword(s):

Immune Responses ◽

Type I Interferon ◽

Innate Immune ◽

Interferon Response ◽

Type I ◽

Response Type ◽

Innate Immune Responses ◽

Interferon Stimulated Genes ◽

Huh7 Cells ◽

Related Proteins

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes Coronavirus disease 2019 (COVID-19) has caused a global health emergency. A key feature of COVID-19 is dysregulated interferon-response. Type-I interferon (IFN-I) is one of the earliest antiviral innate immune responses following viral infection and plays a significant role in the pathogenesis of SARS-CoV-2. In this study, using a proteomics-based approach, we identified that SARS-CoV-2 infection induces delayed and dysregulated IFN-I signaling in Huh7 cells. We demonstrate that SARS-CoV-2 is able to inhibit RIG-I mediated IFN-β production. Our results also confirm the recent findings that IFN-I pretreatment is able to reduce the susceptibility of Huh7 cells to SARS-CoV-2, but not post-treatment. Moreover, senescent Huh7 cells, in spite of showing accentuated IFN-I response were more susceptible to SARS-CoV-2 infection, and the virus effectively inhibited IFIT1 in these cells. Finally, proteomic comparison between SARS-CoV-2, SARS-CoV, and MERS-CoV revealed a distinct differential regulatory signature of interferon-related proteins emphasizing that therapeutic strategies based on observations in SARS-CoV and MERS-CoV should be used with caution. Our findings provide a better understanding of SARS-CoV-2 regulation of cellular interferon response and a perspective on its use as a treatment. Investigation of different interferon-stimulated genes and their role in the inhibition of SARS-CoV-2 pathogenesis may direct novel antiviral strategies.

Download Full-text

Type-I interferon signatures in SARS-CoV-2 infected Huh7 cells

10.1101/2021.02.04.429738 ◽

2021 ◽

Author(s):

Xi Chen ◽

Elisa Saccon ◽

K. Sofia Appelberg ◽

Flora Mikaeloff ◽

Jimmy Esneider Rodriguez ◽

...

Keyword(s):

Immune Responses ◽

Type I Interferon ◽

Innate Immune ◽

Interferon Response ◽

Type I ◽

Response Type ◽

Innate Immune Responses ◽

Interferon Stimulated Genes ◽

Huh7 Cells ◽

Related Proteins

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes Coronavirus disease 2019 (COVID-19) has caused a global health emergency. A key feature of COVID-19 is dysregulated interferon-response. Type-I interferon (IFN-I) is one of the earliest antiviral innate immune responses following viral infection and plays a significant role in the pathogenesis of SARS-CoV-2. In this study, using a proteomics-based approach, we identified that SARS-CoV-2 infection induces delayed and dysregulated IFN-I signaling in Huh7 cells. We demonstrate that SARS-CoV-2 is able to inhibit RIG-I mediated IFN-β production. Our results also confirm the recent findings that IFN-I pretreatment is able to reduce susceptibility of Huh7 cells to SARS-CoV-2, but not post-treatment. Moreover, senescent Huh7 cells, in spite of showing accentuated IFN-I response were more susceptible to SARS-CoV-2 infection, and the virus effectively inhibited IFIT1 in these cells. Finally, proteomic comparison between SARS-CoV-2, SARS-CoV and MERS-CoV revealed a distinct differential regulatory signature of interferon-related proteins emphasizing that therapeutic strategies based on observations in SARS-CoV and MERS-CoV should be used with caution. Our findings provide a better understanding of SARS-CoV-2 regulation of cellular interferon response and a perspective on its use as a treatment. Investigation of different interferon stimulated genes and their role in inhibition of SARS-CoV-2 pathogenesis may direct novel antiviral strategies.

Download Full-text

The Solute Carrier Transporter SLC15A3 Participates in Antiviral Innate Immune Responses against Herpes Simplex Virus-1

Journal of Immunology Research ◽

10.1155/2018/5214187 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Longzhen He ◽

Baocheng Wang ◽

Yuanyuan Li ◽

Leqing Zhu ◽

Peiling Li ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Immune Responses ◽

Innate Immune ◽

Host Cells ◽

Type I ◽

Innate Immune Responses ◽

Herpes Simplex Virus 1 ◽

Simplex Virus ◽

Hsv 1

The innate immune response is the first line defense against viral infections. Novel genes involved in this system are continuing to emerge. SLC15A3, a proton-coupled histidine and di-tripeptide transporter that was previously found in lysosomes, has been reported to inhibit chikungunya viral replication in host cells. In this study, we found that SLC15A3 was significantly induced by DNA virus herpes simplex virus-1(HSV-1) in monocytes from human peripheral blood mononuclear cells. Aside from monocytes, it can also be induced by HSV-1 in 293T, HeLa cells, and HaCaT cells. Overexpression of SLC15A3 in 293T cells inhibits HSV-1 replication and enhances type I and type III interferon (IFN) responses, while silencing SLC15A3 leads to enhanced HSV-1 replication with reduced IFN production. Moreover, we found that SLC15A3 interacted with MAVS and STING and potentiated MAVS- and STING-mediated IFN production. These results demonstrate that SLC15A3 participates in anti-HSV-1 innate immune responses by regulating MAVS- and STING-mediated signaling pathways.

Download Full-text

Cytosolic DNA sensor-initiated innate immune responses in mouse ovarian granulosa cells

Reproduction ◽

10.1530/rep-16-0674 ◽

2017 ◽

Vol 153 (6) ◽

pp. 821-834 ◽

Cited By ~ 4

Author(s):

Keqin Yan ◽

Dingqing Feng ◽

Jing Liang ◽

Qing Wang ◽

Lin Deng ◽

...

Keyword(s):

Immune Responses ◽

Granulosa Cells ◽

Innate Immune ◽

Type I Interferons ◽

Endocrine Function ◽

Type I ◽

Dna Sensor ◽

Innate Immune Responses ◽

Oligoadenylate Synthetase ◽

Ovarian Granulosa Cells

Viral infections of the ovary may perturb ovarian functions. However, the mechanisms underlying innate immune responses in the ovary are poorly understood. The present study demonstrates that cytosolic viral DNA sensor signaling initiates the innate immune response in mouse ovarian granulosa cells and affects endocrine function. The cytosolic DNA sensors p204 and cGAS and their common signaling adaptor stimulator of interferon (IFN) genes (STING) were constitutively expressed in granulosa cells. Transfection with VACV70, a synthetic vaccinia virus (VACV) DNA analog, induced the expression of type I interferons (IFNA/B) and major inflammatory cytokines (TNFA and IL6) through IRF3 and NF-κB activation respectively. Moreover, several IFN-inducible antiviral proteins, including 2′,5′-oligoadenylate synthetase, IFN-stimulating gene 15 and Mx GTPase 1, were also induced by VACV70 transfection. The innate immune responses in granulosa cells were significantly reduced by the transfection of specific small-interfering RNAs targeting p204, cGas or Sting. Notably, the VACV70-triggered innate immune responses affected steroidogenesis in vivo and in vitro. The data presented in this study describe the mechanism underlying ovarian immune responses to viral infection.

Download Full-text

How the Innate Immune DNA Sensing cGAS–STING Pathway Is Involved in Autophagy

International Journal of Molecular Sciences ◽

10.3390/ijms222413232 ◽

2021 ◽

Vol 22 (24) ◽

pp. 13232

Author(s):

Wanglong Zheng ◽

Nengwen Xia ◽

Jiajia Zhang ◽

Nanhua Chen ◽

François Meurens ◽

...

Keyword(s):

Immune Responses ◽

Inflammatory Responses ◽

Complex Interaction ◽

Innate Immune ◽

Type I Interferons ◽

Type I ◽

Innate Immune Responses ◽

Homeostatic Process ◽

Sting Pathway ◽

Dna Complex

The cGAS–STING pathway is a key component of the innate immune system and exerts crucial roles in the detection of cytosolic DNA and invading pathogens. Accumulating evidence suggests that the intrinsic cGAS–STING pathway not only facilitates the production of type I interferons (IFN-I) and inflammatory responses but also triggers autophagy. Autophagy is a homeostatic process that exerts multiple effects on innate immunity. However, systematic evidence linking the cGAS–STING pathway and autophagy is still lacking. Therefore, one goal of this review is to summarize the known mechanisms of autophagy induced by the cGAS–STING pathway and their consequences. The cGAS–STING pathway can trigger canonical autophagy through liquid-phase separation of the cGAS–DNA complex, interaction of cGAS and Beclin-1, and STING-triggered ER stress–mTOR signaling. Furthermore, both cGAS and STING can induce non-canonical autophagy via LC3-interacting regions and binding with LC3. Subsequently, autophagy induced by the cGAS–STING pathway plays crucial roles in balancing innate immune responses, maintaining intracellular environmental homeostasis, alleviating liver injury, and limiting tumor growth and transformation.

Download Full-text

To “Z” or not to “Z”: Z-RNA, self-recognition, and the MDA5 helicase

PLoS Genetics ◽

10.1371/journal.pgen.1009513 ◽

2021 ◽

Vol 17 (5) ◽

pp. e1009513

Author(s):

Alan Herbert

Keyword(s):

Immune Responses ◽

Innate Immune ◽

Type I ◽

Innate Immune Responses ◽

Genetic Elements ◽

Self Recognition ◽

Risc Complex ◽

A Site ◽

Interferon Responses ◽

Rna Formation

Double-stranded RNA (dsRNA) is produced both by virus and host. Its recognition by the melanoma differentiation–associated gene 5 (MDA5) initiates type I interferon responses. How can a host distinguish self-transcripts from nonself to ensure that responses are targeted correctly? Here, I discuss a role for MDA5 helicase in inducing Z-RNA formation by Alu inverted repeat (AIR) elements. These retroelements have highly conserved sequences that favor Z-formation, creating a site for the dsRNA-specific deaminase enzyme ADAR1 to dock. The subsequent editing destabilizes the dsRNA, ending further interaction with MDA5 and terminating innate immune responses directed against self. By enabling self-recognition, Alu retrotransposons, once invaders, now are genetic elements that keep immune responses in check. I also discuss the possible but less characterized roles of the other helicases in modulating innate immune responses, focusing on DExH-box helicase 9 (DHX9) and Mov10 RISC complex RNA helicase (MOV10). DHX9 and MOV10 function differently from MDA5, but still use nucleic acid structure, rather than nucleotide sequence, to define self. Those genetic elements encoding the alternative conformations involved, referred to as flipons, enable helicases to dynamically shape a cell’s repertoire of responses. In the case of MDA5, Alu flipons switch off the dsRNA-dependent responses against self. I suggest a number of genetic systems in which to study interactions between flipons and helicases further.

Download Full-text

Author response: IL-21/type I interferon interplay regulates neutrophil-dependent innate immune responses to Staphylococcus aureus

10.7554/elife.45501.026 ◽

2019 ◽

Author(s):

Rosanne Spolski ◽

Erin E West ◽

Peng Li ◽

Sharon Veenbergen ◽

Sunny Yung ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Immune Responses ◽

Type I Interferon ◽

Innate Immune ◽

Author Response ◽

Type I ◽

Innate Immune Responses

Download Full-text

An Update on Innate Immune Responses during SARS-CoV-2 Infection

Viruses ◽

10.3390/v13102060 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2060

Author(s):

Yu Zhang ◽

Shuaiyin Chen ◽

Yuefei Jin ◽

Wangquan Ji ◽

Weiguo Zhang ◽

...

Keyword(s):

Immune Responses ◽

Innate Immune ◽

Type I Interferons ◽

Organ Injury ◽

Type I ◽

Innate Immune Responses ◽

Innate Immune Signaling ◽

Viral Proteases ◽

Viral Components ◽

The Relationship

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the Coronaviridae family, which is responsible for the COVID-19 pandemic followed by unprecedented global societal and economic disruptive impact. The innate immune system is the body’s first line of defense against invading pathogens and is induced by a variety of cellular receptors that sense viral components. However, various strategies are exploited by SARS-CoV-2 to disrupt the antiviral innate immune responses. Innate immune dysfunction is characterized by the weak generation of type I interferons (IFNs) and the hypersecretion of pro-inflammatory cytokines, leading to mortality and organ injury in patients with COVID-19. This review summarizes the existing understanding of the mutual effects between SARS-CoV-2 and the type I IFN (IFN-α/β) responses, emphasizing the relationship between host innate immune signaling and viral proteases with an insight on tackling potential therapeutic targets.

Download Full-text

Suppression of MDA5-mediated antiviral immune responses by NSP8 of SARS-CoV-2

10.1101/2020.08.12.247767 ◽

2020 ◽

Author(s):

Ziwei Yang ◽

Xiaolin Zhang ◽

Fan Wang ◽

Peihui Wang ◽

Ersheng Kuang ◽

...

Keyword(s):

Immune Responses ◽

Immune Evasion ◽

Type I Interferon ◽

Rna Viruses ◽

Nonstructural Protein ◽

Innate Immune ◽

Mass Casualties ◽

Type I ◽

Innate Immune Responses ◽

Viral Dsrna

AbstractMelanoma differentiation-associated gene-5 (MDA5) acts as a cytoplasmic RNA sensor to detect viral dsRNA and mediates type I interferon (IFN) signaling and antiviral innate immune responses to infection by RNA viruses. Upon recognition of viral dsRNA, MDA5 is activated with K63-linked polyubiquitination and then triggers the recruitment of MAVS and activation of TBK1 and IKK, subsequently leading to IRF3 and NF-κB phosphorylation. Great numbers of symptomatic and severe infections of SARS-CoV-2 are spreading worldwide, and the poor efficacy of treatment with type I interferon and antiviral agents indicates that SARS-CoV-2 escapes from antiviral immune responses via an unknown mechanism. Here, we report that SARS-CoV-2 nonstructural protein 8 (NSP8) acts as an innate immune suppressor and inhibits type I IFN signaling to promote infection of RNA viruses. It downregulates the expression of type I IFNs, IFN-stimulated genes and proinflammatory cytokines by binding to MDA5 and impairing its K63-linked polyubiquitination. Our findings reveal that NSP8 mediates innate immune evasion during SARS-CoV-2 infection and may serve as a potential target for future therapeutics for SARS-CoV-2 infectious diseases.ImportanceThe large-scale spread of COVID-19 is causing mass casualties worldwide, and the failure of antiviral immune treatment suggests immune evasion. It has been reported that several nonstructural proteins of severe coronaviruses suppress antiviral immune responses; however, the immune suppression mechanism of SARS-CoV-2 remains unknown. Here, we revealed that NSP8 protein of SARS-CoV-2 directly blocks the activation of the cytosolic viral dsRNA sensor MDA5 and significantly downregulates antiviral immune responses. Our study contributes to our understanding of the direct immune evasion mechanism of SARS-CoV-2 by showing that NSP8 suppresses the most upstream sensor of innate immune responses involved in the recognition of viral dsRNA.

Download Full-text