We report here the identification and characterization of a protein, ERIS, an endoplasmic reticulum (ER) IFN stimulator, which is a strong type I IFN stimulator and plays a pivotal role in response to both non-self-cytosolic RNA and dsDNA. ERIS (also known as STING or MITA) resided exclusively on ER membrane. The ER retention/ retrieval sequence RIR was found to be critical to retain the protein on ER membrane and to maintain its integrity. ERIS was dimerized on innate immune challenges. Coumermycin-induced ERIS dimerization led to strong and fast IFN induction, suggesting that dimerization of ERIS was critical for self-activation and subsequent downstream signaling.innate immunity ͉ type I IFN ͉ functional cDNA library screening ͉ cytosolic RNA and dsDNA ͉ ER retention signal M icrobial infection-induced host immune responses are initiated by the germline-encoded pattern recognition receptors, which recognize components specific to microorganisms. There are 3 major classes of such receptors: Toll-like receptors (TLRs), RIG-I-like helicases (RLHs) and NOD-like receptors (1). During infection, nucleic acids derived from microbes are recognized by TLRs and RLHs, which then trigger a series of signaling events leading to the production of type I IFNs and proinflammatory cytokines.RLHs have recently been identified to sense the invading viruses in the cytoplasm. Unlike TLRs, which are expressed in specific cells like macrophages and dendritic cells, RLHs are found in most cell types (2). They contain caspase recruitment domain (CARD) and DExD/H helicase domain. RLHs interact with microbial nucleotides through their helicase domain. The N-terminal CARDs are responsible for activating downstream signaling pathways that mediate type I IFN production. Genetic analyses demonstrate that RIG-I and MDA5 sense distinct types of viruses (3-5). RIG-I and MDA5 use a common adaptor molecule, IPS-1 (also known as Cardif, MAVS, or VISA) (6-9). IPS-1 is found to reside on the mitochondrial membrane by its C-terminal transmembrane (TM) domain. It also contains a CARD-like domain at its N-terminus, which mediates the interaction with MDA5 or RIG-I. IPS-1 transmits the signal to TANK-binding kinase-1 (TBK1)/I B kinase i (IKKi; also known as IKK ) and the IKK complex to activate interferon regulatory factor (IRF)-3/IRF-7 and NF-B, respectively, collectively eliciting innate antiviral immune responses, including type I IFN production.On the other hand, dsDNA in the cytosol, for example, genomic DNA from intracellular bacteria (e.g., Listeria, Legionella), also causes a strong host immune response independent of TLRs, leading to the induction of type I IFN. A recent report has indicated that the molecule DAI (also known as ZBP1) might serve as a cytosolic dsDNA sensor (10). However, ZBP1 Ϫ/Ϫ cells showed normal type I IFN production in response to dsDNA stimulation (11). Meanwhile, reports showed that IPS-1/Cardif/MAVS/VISA was not required for dsDNA-caused innate immune activation (12).The signaling induced by cytoplasmic dsDNA leading ...
Viral infection or TLR3 engagement causes activation of the transcription factors IRF-3 and NF-jB, which collaborate to induce transcription of type I IFN genes. IKKe and TBK1 are two IKK-related kinases critically involved in virus-and TLR3-triggered activation of IRF-3. We identified a protein termed SIKE (for Suppressor of IKKe) that interacts with IKKe and TBK1. SIKE is associated with TBK1 under physiological condition and dissociated from TBK1 upon viral infection or TLR3 stimulation. Overexpression of SIKE disrupted the interactions of IKKe or TBK1 with TRIF, RIG-I and IRF-3, components in virus-and TLR3-triggered IRF-3 activation pathways, but did not disrupt the interactions of TRIF with TRAF6 and RIP, components in TLR3-triggered NF-jB activation pathway. Consistently, overexpression of SIKE inhibited virus-and TLR3-triggered interferon-stimulated response elements (ISRE) but not NF-jB activation. Knockdown of SIKE potentiated virus-and TLR3-triggered ISRE but not NF-jB activation. Moreover, overexpression of SIKE inhibited IKKe-and TBK1-mediated antiviral response. These findings suggest that SIKE is a physiological suppressor of IKKe and TBK1 and plays an inhibitory role in virus-and TLR3-triggered IRF-3 but not NF-jB activation pathways.
RIG-I and MDA5 are cytoplasmic sensors that recognize different species of viral RNAs, leads to activation of the transcription factors IRF3 and NF-κB, which collaborate to induce type I interferons. In this study, we identified REUL, a RING-finger protein, as a specific RIG-I-interacting protein. REUL was associated with RIG-I, but not MDA5, through its PRY and SPRY domains. Overexpression of REUL potently potentiated RIG-I-, but not MDA5-mediated downstream signalling and antiviral activity. In contrast, the RING domain deletion mutant of REUL suppressed Sendai virus (SV)-induced, but not cytoplasmic polyI:C-induced activation of IFN-β promoter. Knockdown of endogenous REUL by RNAi inhibited SV-triggered IFN-β expression, and also increased VSV replication. Full-length RIG-I, but not the CARD domain deletion mutant of RIG-I, underwent ubiquitination induced by REUL. The Lys 154, 164, and 172 residues of the RIG-I CARD domain were critical for efficient REUL-mediated ubiquitination, as well as the ability of RIG-I to induce activation of IFN-β promoter. These findings suggest that REUL is an E3 ubiquitin ligase of RIG-I and specifically stimulates RIG-I-mediated innate antiviral activity.
Viral infection leads to activation of the transcription factors interferon regulatory factor-3 and NF-B, which collaborate to induce type I IFNs. The RNA helicase proteins RIG-I and MDA5 were recently identified as two cytoplasmic viral RNA sensors that recognize different species of viral RNAs produced during viral replication. In this study, we identified DAK, a functionally unknown dihydroacetone kinase, as a specific MDA5-interacting protein. DAK was associated with MDA5, but not RIG-I, under physiological conditions. Overexpression of DAK inhibited MDA5-but not RIG-I-or TLR3-mediated IFN- induction. Overexpression of DAK also inhibited cytoplasmic dsRNA and SeV-induced activation of the IFN- promoter, whereas knockdown of endogenous DAK by RNAi activated the IFN- promoter, and increased cytoplasmic dsRNA-or SeV-triggered activation of the IFN- promoter. In addition, overexpression of DAK inhibited MDA5-but not RIG-Imediated antiviral activity, whereas DAK RNAi increased cytoplasmic dsRNA-triggered antiviral activity. These findings suggest that DAK is a physiological suppressor of MDA5 and specifically inhibits MDA5-but not RIG-I-mediated innate antiviral signaling. The innate immune system has developed at least two distinct mechanisms for the recognition of viral RNAs (2, 3, 9). One is mediated by Toll-like receptor 3 (TLR3), which recognizes viral dsRNA released by infected cells (10). Engagement of TLR3 by dsRNA triggers TRIF-mediated signaling pathways, leading to IRF-3 and NF-B activation (11-16). The second mechanism involves two RNA helicase proteins, RIG-I and MDA5, which function as cytoplasmic viral RNA sensors (17, 18). Both RIG-I and MDA5 contain two CARD modules at their N terminus and a DexD/H-box helicase domain at their C terminus. The helicase domains of RIG-I and MDA5 serve as intracellular viral RNA receptors, whereas the CARD modules are responsible for transmitting signals to downstream CARD-containing adaptor VISA/ MAVS/IPS-1/Cardif, which in turn activates TAK1-IKK and TBK1/IKK kinases, leading to activation of NF-B and IRF-3 and induction of type I IFNs (19)(20)(21)(22)(23)(24).Although MDA5 and RIG-I share a similar structural architecture, and their signaling pathways converge at the adaptor level, gene-knockout studies indicate that the two proteins are required for responding to distinct species of RNA viruses. RIG-I responds to in vitro-transcribed dsRNA, vesicular stomatitis virus (VSV), Newcastle disease virus, and influenza virus in mice. In contrast, MDA5 recognizes poly(I:C) and is essential for the antiviral response to the picornavirus encephalomyocarditis virus (25,26). Recently, it was demonstrated that RIG-I, but not MDA5, recognizes single-strand RNA bearing 5Ј phosphate (27,28). In addition, it has been shown that signaling mediated by RIG-I-and MDA5-mediated signaling is differentially regulated. For example, the V protein of paramyxovirus appears to selectively target MDA5-but not RIG-I-mediated IFN response (29)(30)(31).In the present study, we identified D...
Fear is a negative emotional reaction to or persistent worry over an imminent public health event like COVID-19. The COVID-Fear Scale was developed in many countries, but not in China. The current study aims to examine the psychometric properties of Chinese version of the Fear of COVID-19 Scale. Translation into Chinese and backtranslation into English were conducted firstly. Item analysis and exploratory factor analysis were conducted in Sample 1, followed by validity tests in Sample 2. Likely, test-retest reliability was conducted in sample 3. A bifactor structure of Chinese version of FCV-19S with a general fear factor and two orthogonal group factors with fear thoughts and physical response was confirmed. Besides, it has good internal consistency reliability (α = .92), composite reliability (CR = .92), and validity correlation validity. The results of the present study confirmed that the Chinese version of FCV-19S has good psychometric properties in the Chinese communities. Keywords Fear of COVID-19 Scale. Reliability. Validity Coronavirus disease 2019 (COVID-19) is a novel and highly infectious respiratory disease, which has threatened to become a global public health crisis (Cucinotta and Vanelli 2020). Specifically, the COVID-19 has affected 215 countries till July 13, 2020, and the number of confirmed cases has exceeded 12.95 million with 560,000 registered deaths worldwide (Worldometers 2020). In China, approximately 80,000 individuals have been diagnosed with COVID-19, with over 4600 officially recorded deaths (Chinese National Health Commission 2020). Such substantial negative effects or damage caused by COVID-19 are not simply observed on the global economy (Al-Awadhi et al. 2020; Laing 2020), but this pandemic is also affecting mental health (e.g., depression, anxiety, and fear) across a variety of age groups and cultural backgrounds (Liu et al. 2020; Rajkumar 2020).
The administration of COVID-19 vaccines is the primary strategy used to prevent further infections by COVID-19, especially in people living with HIV (PLWH), who are at increased risk for severe symptoms and mortality. However, the vaccine hesitancy, safety, and immunogenicity of COVID-19 vaccines among PLWH have not been fully characterized. We estimated vaccine hesitancy and status of COVID-19 vaccination in Chinese PLWH, explored the safety and impact on antiviral therapy (ART) efficacy and compared the immunogenicity of an inactivated vaccine between PLWH and healthy controls (HC). In total, 27.5% (104/378) of PLWH hesitated to take the vaccine. The barriers included concerns about safety and efficacy, and physician counselling might help patients overcome this vaccine hesitancy. A COVID-19 vaccination did not cause severe side effects and had no negative impact on CD4+ T cell counts and HIV RNA viral load. Comparable spike receptor binding domain IgG titer were elicited in PLWH and HC after a second dose of the CoronaVac vaccine, but antibody responses were lower in poor immunological responders (CD4+ T cell counts < 350 cells/µL) compared with immunological responders (CD4+ T cell counts ≥ 350 cells/µL). These data showed that PLWH have comparable safety and immune response following inactivated COVID-19 vaccination compared with HC, but the poor immunological response in PLWH is associated with impaired humoral response.
Receptor-interacting protein (RIP) is a serine/threonine protein kinase that is critically involved in tumor necrosis factor receptor-1 (TNF-R1)-induced NF-B activation. In a yeast two-hybrid screening for potential RIP-interacting proteins, we identified ZIN (zinc finger protein inhibiting NF-B), a novel protein that specifically interacts with RIP. ZIN contains four RING-like zinc finger domains at the middle and a proline-rich domain at the C terminus. Overexpression of ZIN inhibits RIP-, IKK-, TNF-, and IL1-induced NF-B activation in a dose-dependent manner in 293 cells. Domain mapping experiments indicate that the RING-like zinc finger domains of ZIN are required for its interaction with RIP and inhibition of RIP-mediated NF-B activation. Overexpression of ZIN also potentiates RIP-and TNF-induced apoptosis. Moreover, immunofluorescent staining indicates that ZIN is a cytoplasmic protein and that it colocalizes with RIP. Our findings suggest that ZIN is an inhibitor of TNF-and IL1-induced NF-B activation pathways. Tumor necrosis factor receptor 1 (TNF-R1)1 is a prototypical member of the TNF receptor family (1). TNF stimulation of TNF-R1 simultaneously induces three divergent effects: apoptosis, activation of the transcription factor NF-B, and the serine/threonine protein kinase JNK (1). TNF-R1 contains a death domain, which interacts with the cytoplasmic death domain-containing protein TRADD in a TNF-dependent process (2-5). Once TRADD is recruited to TNF-R1, it functions as an adapter protein to recruit several structurally and functionally divergent proteins, including FADD, RIP, TRAF2, and cellular inhibitor of apoptosis protein (cIAP) (2, 4). The interaction of TRADD with FADD leads to apoptosis through activation of a caspase cascade, which is initiated by the interaction of FADD with caspase-8 (2, 6 -10). The interaction of TRADD with TRAF2 and RIP activates a downstream IB kinase complex called IKK, which contains two catalytic subunits, IKK␣ and IKK, and a regulatory subunit, IKK␥/NEMO (11-19). The activated IKK phosphorylates IBs, leading to their degradation and subsequent activation of NF-B (11-19).RIP is a unique signal transducer in the TNF-R1-mediated NF-B activation pathway. RIP was first identified as a Fasinteracting protein by the yeast two-hybrid system (20). It was later demonstrated that RIP is a component of the TNF-R1 signaling complex (4, 21). Gene knock-out experiments suggest that RIP is required for TNF-R1-mediated NF-B activation but is not required for Fas-and TNF-R1-mediated apoptosis (22,23). RIP is a serine/threonine kinase that contains three domains, including an N-terminal kinase domain, an intermediate domain, and a C-terminal death domain (4,20). RIP interacts with TRADD through their respective death domains. The intermediate domain of RIP interacts with the RING finger domain of TRAF2, and this interaction is required for RIP-mediated NF-B activation (21). Recently, it has been suggested that RIP directly interacts with IKK␥ and therefore recruits IKK to the TNF-R1 c...
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