scholarly journals The Laboratory of Genetics and Physiology 2: Emerging Insights into the Controversial Functions of This RIG-I-Like Receptor

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Zixiang Zhu ◽  
Xiangle Zhang ◽  
Guoqing Wang ◽  
Haixue Zheng
Keyword(s):  
Immune Responses ◽  
Functional Performance ◽  
Signaling Proteins ◽  
Rna Recognition ◽  
Innate Immune Responses ◽  
Downstream Signaling ◽  
Regulation Mechanisms ◽  
Structure And Functions ◽  
Insight Into ◽  
Inducible Gene

The laboratory of genetics and physiology 2 (LGP2) is a key component of the RNA helicase family of retinoic acid-inducible gene 1- (RIG-I-) like receptors (RLRs) and is widely involved in viral RNA recognition and regulation during innate immune responses. Unlike RIG-I and melanoma differentiation-associated 5, both RLR members, LGP2 lacks the caspase-recruitment domain (CARD), which is required for recruiting and interacting with downstream signaling proteins to activate a cascade of downstream signaling events. The absence of the CARD results in divergent functional performance for LGP2 compared to these other RLR members. Both negative and positive regulatory roles have been reported for LGP2 in antiviral immune responses. It is currently unclear how the unusual properties of LGP2 mediate opposing roles. Future studies should elucidate the molecular mechanism(s) of LGP2 action. This minireview provides a brief overview of LGP2 structure and functions, with an expanded discussion on the regulation mechanisms in response to viral infection, hopefully stimulating insight into the divergent roles of LGP2 in the regulation of antiviral immune responses.

scholarly journals Immunologic Consequences of Hypoxia during Critical Illness

2016 ◽  
Vol 125 (1) ◽  
pp. 237-249 ◽  
Author(s):  
Harmke D. Kiers ◽  
Gert-Jan Scheffer ◽  
Johannes G. van der Hoeven ◽  
Holger K. Eltzschig ◽  
Peter Pickkers ◽  
...  
Keyword(s):  
Immune Responses ◽  
Signaling Pathways ◽  
Daily Practice ◽  
Innate Immune ◽  
Protective Effects ◽  
Innate Immune Responses ◽  
Downstream Signaling ◽  
Pathogen Clearance ◽  
Pharmacologic Modulation ◽  
Oxygen Status

Abstract Hypoxia and immunity are highly intertwined at clinical, cellular, and molecular levels. The prevention of tissue hypoxia and modulation of systemic inflammation are cornerstones of daily practice in the intensive care unit. Potentially, immunologic effects of hypoxia may contribute to outcome and represent possible therapeutic targets. Hypoxia and activation of downstream signaling pathways result in enhanced innate immune responses, aimed to augment pathogen clearance. On the other hand, hypoxia also exerts antiinflammatory and tissue-protective effects in lymphocytes and other tissues. Although human data on the net immunologic effects of hypoxia and pharmacologic modulation of downstream pathways are limited, preclinical data support the concept of tailoring the immune response through modulation of the oxygen status or pharmacologic modulation of hypoxia-signaling pathways in critically ill patients.

scholarly journals Toll-like receptor 3 (TLR3) regulation mechanisms and roles in antiviral innate immune responses

2021 ◽  
Vol 22 (8) ◽  
pp. 609-632
Author(s):  
Yujuan Chen ◽  
Junhong Lin ◽  
Yao Zhao ◽  
Xianping Ma ◽  
Huashan Yi
Keyword(s):  
Immune Responses ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Toll Like Receptor ◽  
Regulation Mechanisms

scholarly journals An Evaluation of the Fasciola hepatica miRnome Predicts a Targeted Regulation of Mammalian Innate Immune Responses

2021 ◽  
Vol 11 ◽  
Author(s):  
Alison Ricafrente ◽  
Hieu Nguyen ◽  
Nham Tran ◽  
Sheila Donnelly
Keyword(s):  
Immune Responses ◽  
Immune Cell ◽  
Fasciola Hepatica ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Regulate Gene Expression ◽  
Non Coding Rnas ◽  
Parasitic Worms ◽  
High Degree ◽  
Insight Into

Understanding mechanisms by which parasitic worms (helminths) control their hosts’ immune responses is critical to the development of effective new disease interventions. Fasciola hepatica, a global scourge of humans and their livestock, suppresses host innate immune responses within hours of infection, ensuring that host protective responses are quickly incapacitated. This allows the parasite to freely migrate from the intestine, through the liver to ultimately reside in the bile duct, where the parasite establishes a chronic infection that is largely tolerated by the host. The recent identification of micro(mi)RNA, small RNAs that regulate gene expression, within the extracellular vesicles secreted by helminths suggest that these non-coding RNAs may have a role in the parasite-host interplay. To date, 77 miRNAs have been identified in F. hepatica comprising primarily of ancient conserved species of miRNAs. We hypothesized that many of these miRNAs are utilized by the parasite to regulate host immune signaling pathways. To test this theory, we first compiled all of the known published F. hepatica miRNAs and critically curated their sequences and annotations. Then with a focus on the miRNAs expressed by the juvenile worms, we predicted gene targets within human innate immune cells. This approach revealed the existence of targets within every immune cell, providing evidence for the universal management of host immunology by this parasite. Notably, there was a high degree of redundancy in the potential for the parasite to regulate the activation of dendritic cells, eosinophils and neutrophils, with multiple miRNAs predicted to act on singular gene targets within these cells. This original exploration of the Fasciola miRnome offers the first molecular insight into mechanisms by which F. hepatica can regulate the host protective immune response.

cGAS-STING-mediated IFN-I response in host defense and neuro-inflammatory diseases

2021 ◽  
Vol 19 ◽  
Author(s):  
Kai Chen ◽  
Chuan Lai ◽  
Yin Su ◽  
Wen Dai Bao ◽  
Liu Nan Yang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Host Defense ◽  
Inflammatory Diseases ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Danger Signal ◽  
Downstream Signaling ◽  
Pathway Activation ◽  
Sting Pathway ◽  
Lateral Sclerosis

: The presence of foreign or misplaced nucleic acids is a danger signal that triggers innate immune responses through activating cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) and binding to its downstream signaling effector stimulator of interferon genes (STING). Then the cGAS–STING pathway activation links nucleic acid sensing to immune responses and pathogenic entities clearance. However, overactivation of this signaling pathway leads to fatal immune disorders and contributes to the progression of many human inflammatory diseases. Therefore, optimal activation of this pathway is crucial for the elimination of invading pathogens and the maintenance of immune homeostasis. In this review, we will summarize its fundamental roles in initiating host defense against invading pathogens and discuss its pathogenic roles in multiple neuro-inflammatory diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and other neurodegenerative diseases.

scholarly journals Unique and complementary suppression of cGAS-STING and RNA sensing- triggered innate immune responses by SARS-CoV-2 proteins

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Yajuan Rui ◽  
Jiaming Su ◽  
Si Shen ◽  
Ying Hu ◽  
Dingbo Huang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Nuclear Factor Κb ◽  
Innate Immune ◽  
Nuclear Accumulation ◽  
Innate Immune Responses ◽  
Structural Protein ◽  
Viral Protease ◽  
Downstream Signaling ◽  
Efficient Replication

AbstractThe emergence of SARS-CoV-2 has resulted in the COVID-19 pandemic, leading to millions of infections and hundreds of thousands of human deaths. The efficient replication and population spread of SARS-CoV-2 indicates an effective evasion of human innate immune responses, although the viral proteins responsible for this immune evasion are not clear. In this study, we identified SARS-CoV-2 structural proteins, accessory proteins, and the main viral protease as potent inhibitors of host innate immune responses of distinct pathways. In particular, the main viral protease was a potent inhibitor of both the RLR and cGAS-STING pathways. Viral accessory protein ORF3a had the unique ability to inhibit STING, but not the RLR response. On the other hand, structural protein N was a unique RLR inhibitor. ORF3a bound STING in a unique fashion and blocked the nuclear accumulation of p65 to inhibit nuclear factor-κB signaling. 3CL of SARS-CoV-2 inhibited K63-ubiquitin modification of STING to disrupt the assembly of the STING functional complex and downstream signaling. Diverse vertebrate STINGs, including those from humans, mice, and chickens, could be inhibited by ORF3a and 3CL of SARS-CoV-2. The existence of more effective innate immune suppressors in pathogenic coronaviruses may allow them to replicate more efficiently in vivo. Since evasion of host innate immune responses is essential for the survival of all viruses, our study provides insights into the design of therapeutic agents against SARS-CoV-2.

scholarly journals Picornavirus 3C proteins inhibit RIG-I-mediated innate immune responses by reducing TRIM25 expression

2020 ◽  
Author(s):  
Huimin Xiao ◽  
Jingliang Li ◽  
Xu Yang ◽  
Zhaolong Li ◽  
Yajuan Rui ◽  
...  
Keyword(s):  
Immune Responses ◽  
Innate Immune ◽  
Luciferase Reporter ◽  
Type I ◽  
Innate Immune Responses ◽  
Protease Cleavage ◽  
Structural Conformation ◽  
Reporter Assays ◽  
Retinoid Acid ◽  
Inducible Gene

Abstract Background：Enterovirus (EV) 3C proteins suppress type I interferon (IFN) responses mediated by retinoid acid-inducible gene I (RIG-I). An E3 ubiquitin ligase, tripartite motif protein 25 (TRIM25)-mediated RIG-I ubiquitination is essential for RIG-I antiviral activity. However, whether the effect of EV 3C on RIG-I is associated with TRIM25 remains unknown.Methods：In this study，luciferase reporter assays was used to detected the activity of IFN-β. Western Blot was used to detected the expression of proteins. Real-time PCR are used to detect that the mRNAs expression. And the co-immunoprecipitation assay was used to detect the interaction between TRIM25 and 3C protein.Results：Here, we demonstrated that 3C proteins of EV71 and CVB3 reduced the expression of RIG-I and TRIM25 through protease cleavage activities. Overexpression of TRIM25 restored RIG-I expression and IFN production reduced by 3C proteins. Further investigation confirmed that the two amino acids in TRIM25 required for RIG-I ubiquitination and structural conformation of TRIM25 were essential for RIG-I recovery. Moreover, we observed that TRIM25 could rescue RIG-I expression reduced by CVA6and EVD68 but not CVA16 3C.Conclusions：Our findings provide an insightful interpretation of 3C protein-mediated host innate immune suppression and support TRIM25 as an attractive target against EV infection.

scholarly journals ALG2 regulates type I interferon responses by inhibiting STING trafficking

2021 ◽  
Author(s):  
Wangsheng Ji ◽  
Lianfei Zhang ◽  
Xiaoyu Xu ◽  
Xinqi Liu
Keyword(s):  
Immune Responses ◽  
Type I Interferon ◽  
Innate Immune ◽  
Type I Interferons ◽  
Interferon Response ◽  
Type I ◽  
Innate Immune Responses ◽  
Downstream Signaling ◽  
Interferon Responses ◽  
Hsv 1

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.

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