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12 pages, 9785 KiB

Open AccessArticle

Absent in Melanoma 2 Mediates Inflammasome Signaling Activation against Clostridium perfringens Infection

by Zhaoguo Ma, Yanan Lou, Na Wang, Yi Zhao, Shuxin Zhang, Mingyue Zhang, Jiaqi Li, Qian Xu, Aobo He and Shuixing Yu

Int. J. Mol. Sci. 2024, 25(12), 6571; https://doi.org/10.3390/ijms25126571 - 14 Jun 2024

Viewed by 1545

Abstract

Absent in melanoma 2 (AIM2), a key component of the IFI20X/IFI16 (PYHIN) protein family, is characterized as a DNA sensor to detect cytosolic bacteria and DNA viruses. However, little is known about its immunological role during pathogenic Clostridium perfringens (C. perfringens) infection, an extracellular bacterial pathogen. In a pathogenic C. perfringens gas gangrene model, Aim2^−/− mice are more susceptible to pathogenic C. perfringens soft tissue infection, revealing the importance of AIM2 in host protection. Notably, Aim2 deficiency leads to a defect in bacterial killing and clearance. Our in vivo and in vitro findings further establish that inflammasome signaling is impaired in the absence of Aim2 in response to pathogenic C. perfringens. Mechanistically, inflammasome signaling downstream of active AIM2 promotes pathogen control. Importantly, pathogenic C. perfringens-derived genomic DNA triggers inflammasome signaling activation in an AIM2-dependent manner. Thus, these observations uncover a central role for AIM2 in host defense and triggering innate immunity to combat pathogenic C. perfringens infections. Full article

(This article belongs to the Section Molecular Immunology)

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15 pages, 4162 KiB

Open AccessArticle

A Variety of Mouse PYHIN Proteins Restrict Murine and Human Retroviruses

by Sümeyye Erdemci-Evin, Matteo Bosso, Veronika Krchlikova, Wibke Bayer, Kerstin Regensburger, Martha Mayer, Ulf Dittmer, Daniel Sauter, Dorota Kmiec and Frank Kirchhoff

Viruses 2024, 16(4), 493; https://doi.org/10.3390/v16040493 - 23 Mar 2024

Cited by 1 | Viewed by 1885

Abstract

PYHIN proteins are only found in mammals and play key roles in the defense against bacterial and viral pathogens. The corresponding gene locus shows variable deletion and expansion ranging from 0 genes in bats, over 1 in cows, and 4 in humans to a maximum of 13 in mice. While initially thought to act as cytosolic immune sensors that recognize foreign DNA, increasing evidence suggests that PYHIN proteins also inhibit viral pathogens by more direct mechanisms. Here, we examined the ability of all 13 murine PYHIN proteins to inhibit HIV-1 and murine leukemia virus (MLV). We show that overexpression of p203, p204, p205, p208, p209, p210, p211, and p212 strongly inhibits production of infectious HIV-1; p202, p207, and p213 had no significant effects, while p206 and p214 showed intermediate phenotypes. The inhibitory effects on infectious HIV-1 production correlated significantly with the suppression of reporter gene expression by a proviral Moloney MLV-eGFP construct and HIV-1 and Friend MLV LTR luciferase reporter constructs. Altogether, our data show that the antiretroviral activity of PYHIN proteins is conserved between men and mice and further support the key role of nuclear PYHIN proteins in innate antiviral immunity. Full article

(This article belongs to the Special Issue Innate Sensing and Restriction of Retroviruses)

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21 pages, 1557 KiB

Open AccessReview

Role of NLRP3 Inflammasome Activation in Obesity-Mediated Metabolic Disorders

by Kaiser Wani, Hind AlHarthi, Amani Alghamdi, Shaun Sabico and Nasser M. Al-Daghri

Int. J. Environ. Res. Public Health 2021, 18(2), 511; https://doi.org/10.3390/ijerph18020511 - 10 Jan 2021

Cited by 73 | Viewed by 6955

Abstract

NLRP3 inflammasome is one of the multimeric protein complexes of the nucleotide-binding domain, leucine-rich repeat (NLR)-containing pyrin and HIN domain family (PYHIN). When activated, NLRP3 inflammasome triggers the release of pro-inflammatory interleukins (IL)-1β and IL-18, an essential step in innate immune response; however, defective checkpoints in inflammasome activation may lead to autoimmune, autoinflammatory, and metabolic disorders. Among the consequences of NLRP3 inflammasome activation is systemic chronic low-grade inflammation, a cardinal feature of obesity and insulin resistance. Understanding the mechanisms involved in the regulation of NLRP3 inflammasome in adipose tissue may help in the development of specific inhibitors for the treatment and prevention of obesity-mediated metabolic diseases. In this narrative review, the current understanding of NLRP3 inflammasome activation and regulation is highlighted, including its putative roles in adipose tissue dysfunction and insulin resistance. Specific inhibitors of NLRP3 inflammasome activation which can potentially be used to treat metabolic disorders are also discussed. Full article

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17 pages, 3865 KiB

Open AccessReview

Emerging Role of PYHIN Proteins as Antiviral Restriction Factors

by Matteo Bosso and Frank Kirchhoff

Viruses 2020, 12(12), 1464; https://doi.org/10.3390/v12121464 - 18 Dec 2020

Cited by 17 | Viewed by 4390

Abstract

Innate immune sensors and restriction factors are cellular proteins that synergize to build an effective first line of defense against viral infections. Innate sensors are usually constitutively expressed and capable of detecting pathogen-associated molecular patterns (PAMPs) via specific pattern recognition receptors (PRRs) to stimulate the immune response. Restriction factors are frequently upregulated by interferons (IFNs) and may inhibit viral pathogens at essentially any stage of their replication cycle. Members of the Pyrin and hematopoietic interferon-inducible nuclear (HIN) domain (PYHIN) family have initially been recognized as important sensors of foreign nucleic acids and activators of the inflammasome and the IFN response. Accumulating evidence shows, however, that at least three of the four members of the human PYHIN family restrict viral pathogens independently of viral sensing and innate immune activation. In this review, we provide an overview on the role of human PYHIN proteins in the innate antiviral immune defense and on viral countermeasures. Full article

(This article belongs to the Special Issue Intrinsic Antiviral Factors)

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19 pages, 1405 KiB

Open AccessReview

PYHIN Proteins and HPV: Role in the Pathogenesis of Head and Neck Squamous Cell Carcinoma

by Giuseppe Riva, Matteo Biolatti, Giancarlo Pecorari, Valentina Dell’Oste and Santo Landolfo

Microorganisms 2020, 8(1), 14; https://doi.org/10.3390/microorganisms8010014 - 20 Dec 2019

Cited by 18 | Viewed by 7455

Abstract

In the last decades, the human papillomavirus (HPV) emerged as an etiological cause of head and neck squamous cell carcinoma (HNSCC), especially in the oropharynx. The role of two intracellular DNA sensors, which belong to the PYHIN family (interferon-inducible protein 16 (IFI16) and absent in melanoma 2 protein (AIM2)), has been analyzed in relation to HPV infection and head and neck carcinogenesis. In particular, IFI16 and AIM2 expression depends on HPV infection in HNSCC. They represent viral restriction factors and are key components of the intrinsic immunity activated against different viruses, including HPV. This review analyzed and summarized the recent findings about the role of PYHIN proteins in HPV⁺ and HPV⁻ HNSCC. Full article

(This article belongs to the Special Issue Virus-Host Interaction: From Physiology to Pathology)

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19 pages, 1441 KiB

Open AccessReview

Regulation and Sensing of Inflammasomes and Their Impact on Intestinal Health

by Nicole Ranson, Dale Kunde and Rajaraman Eri

Int. J. Mol. Sci. 2017, 18(11), 2379; https://doi.org/10.3390/ijms18112379 - 9 Nov 2017

Cited by 29 | Viewed by 6229

Abstract

Pattern recognition receptors such as nucleotide-binding oligomerization domain (NOD)-containing protein receptors (NLRs) and the pyrin and hematopoitic interferon-inducible nuclear protein (HIN) domain (PYHIN) receptors initiate the inflammatory response following cell stress or pathogenic challenge. When activated, some of these receptors oligomerize to form the structural backbone of a signalling platform known as an inflammasome. Inflammasomes promote the activation of caspase-1 and the maturation of the proinflammatory cytokines, interleukin (IL)-1β and IL-18. The gut dysregulation of the inflammasome complex is thought to be a contributing factor in the development of inflammatory bowel diseases (IBD), such as ulcerative colitis (UC) and Crohn’s disease (CD). The importance of inflammasomes to intestinal health has been emphasized by various inflammasome-deficient mice in dextran sulphate sodium (DSS) models of intestinal inflammation and by the identification of novel potential candidate genes in population-based human studies. In this review, we summarise the most recent findings with regard to the formation, sensing, and regulation of the inflammasome complex and highlight their importance in maintaining intestinal health. Full article

(This article belongs to the Special Issue Inflammation and Cancer 2018)

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