TMEM173 variants and potential importance to human biology and disease

Patel, Seema; Jin, Lei

doi:10.1038/s41435-018-0029-9

Cited by 94 publications

(100 citation statements)

References 76 publications

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“…One example is in species‐specific polymorphisms found in innate immune signalling proteins, as is the case with STING. Although bacterial c‐di‐AMP is a potent inducer of mouse STING, it is less potent at activating certain human STING variants (Patel & Jin, ).…”

Section: Future Directionsmentioning

confidence: 99%

Why isListeria monocytogenessuch a potent inducer of CD8+ T‐cells?

Chávez‐Arroyo

Portnoy

2020

Cellular Microbiology

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Listeria monocytogenes is a rapidly growing, Gram‐positive, facultative intracellular pathogen that has been used for over 5 decades as a model to study basic aspects of infection and immunity. In a murine intravenous infection model, immunisation with a sublethal infection of L. monocytogenes initially leads to rapid intracellular multiplication followed by clearance of the bacteria and ultimately culminates in the development of long‐lived cell‐mediated immunity (CMI) mediated by antigen‐specific CD8+ cytotoxic T‐cells. Importantly, effective immunisation requires live, replicating bacteria. In this review, we summarise the cell and immunobiology of L. monocytogenes infection and discuss aspects of its pathogenesis that we suspect lead to robust CMI. We suggest five specific features of L. monocytogenes infection that positively impact the development of CMI: (a) the bacteria have a predilection for professional antigen‐presenting cells; (b) the bacteria escape from phagosomes, grow, and secrete antigens into the host cell cytosol; (c) bacterial‐secreted proteins enter the major histocompatibility complex (MHC) class I pathway of antigen processing and presentation; (d) the bacteria do not induce rapid host cell death; and (e) cytosolic bacteria induce a cytokine response that favours CMI. Collectively, these features make L. monocytogenes an attractive vaccine vector for both infectious disease applications and cancer immunotherapy.

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Section: Future Directionsmentioning

confidence: 99%

Why isListeria monocytogenessuch a potent inducer of CD8+ T‐cells?

Chávez‐Arroyo

Portnoy

2020

Cellular Microbiology

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“…Gain-of-function mutations in the TMEM173 gene (encoding STING) lead to a newly classified autoinflammatory disease called STING-associated vasculopathy with onset in infancy (SAVI). 50,135,136 SAVI is an autosomaldominant disease characterized by systemic inflammation, severe skin vasculopathy, interstitial lung disease, and recurrent bacterial infection. 50,135,136 De novo and inherited TMEM173 mutations were found in SAVI patients.…”

Section: A Unique Type I Interferonopathy With Lung Manifestation Imentioning

confidence: 99%

“…50,135,136 SAVI is an autosomaldominant disease characterized by systemic inflammation, severe skin vasculopathy, interstitial lung disease, and recurrent bacterial infection. 50,135,136 De novo and inherited TMEM173 mutations were found in SAVI patients. De novo TMEM173 mutations manifest as an early-onset (within the first 8 weeks of life) and severe phenotype, whereas inherited TMEM173 mutations manifested as a late-onset and mild phenotype.…”

Section: A Unique Type I Interferonopathy With Lung Manifestation Imentioning

confidence: 99%

“…De novo TMEM173 mutations manifest as an early-onset (within the first 8 weeks of life) and severe phenotype, whereas inherited TMEM173 mutations manifested as a late-onset and mild phenotype. 50,135,136 In 2014, Liu et al first reported SAVI caused by de novo N154S, V155M or V147L heterozygous missense mutation in TMEM173 in six unrelated children. 50 During the same year, Jeremiah et al reported SAVI with inherited V155M heterozygous mutation in TMEM173 in four individuals of a family.…”

Section: A Unique Type I Interferonopathy With Lung Manifestation Imentioning

confidence: 99%

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The cGAS‐STING pathway: The role of self‐DNA sensing in inflammatory lung disease

Serrano

Davis

et al. 2020

FASEB j.

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The presence of DNA in the cytosol is usually a sign of microbial infections, which alerts the host innate immune system to mount a defense response. Cyclic GMP‐AMP synthase (cGAS) is a critical cytosolic DNA sensor that elicits robust innate immune responses through the production of the second messenger, cyclic GMP‐AMP (cGAMP), which binds and activates stimulator of interferon genes (STING). However, cGAS binds to DNA irrespective of DNA sequence, therefore, self‐DNA leaked from the nucleus or mitochondria can also serve as a cGAS ligand to activate this pathway and trigger extensive inflammatory responses. Dysregulation of the cGAS‐STING pathway is responsible for a broad array of inflammatory and autoimmune diseases. Recently, evidence has shown that self‐DNA release and cGAS‐STING pathway over‐activation can drive lung disease, making this pathway a promising therapeutic target for inflammatory lung disease. Here, we review recent advances on the cGAS‐STING pathway governing self‐DNA sensing, highlighting its role in pulmonary disease.

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“…Several allelic variants of STING can be found in the general population (26), some of which appear to have altered function. The two most common minor allelic variants are R232H and R71H-G230A-R293Q (HAQ).…”

Section: Introductionmentioning

confidence: 99%

Selective Loss of Responsiveness to Exogenous but Not Endogenous Cyclic-Dinucleotides in Mice Expressing STING-R231H

et al. 2020

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Stimulator of interferon genes (STING) plays a central role in innate immune responses to viral and intracellular bacterial infections, and cellular damage. STING is a cytosolic sensor of cyclic dinucleotides (CDNs) including those produced by pathogenic bacteria and those arising endogenously as products of the DNA sensor cGAS (e.g., 2 ′ 3 ′ cGAMP). The two most common alternative allelic variants of STING in humans are STING-R71H-G230A-R293Q (STING-HAQ) and STING-R232H that are found in 20.4% and 13.7-17.6% of the population, respectively. To determine the biologic consequences of these genotypic variations, we generated knock-in mice containing the murine equivalents of each variant and studied their responsiveness to CDNs. Homozygous STING-HAQ (R71H-I229A-R292Q) and STING-R231H mice were found to be unresponsive to all exogenous CDNs tested (ci-di-GMP, ci-di-AMP, 3 ′ 3 ′ cGAMP and Rp,Rp-CDA). Responses of homozygous STING-HAQ mice to endogenous 2 ′ 3 ′ cGAMP was also greatly impaired. However, homozygous STING-R231H mice are fully responsive to 2 ′ 3 ′ cGAMP. Analysis of heterozygous mice revealed reduced responsiveness to exogenous and endogenous CDNs in mice carrying a single copy of STING-HAQ, while STING-R231H heterozygous mice exhibit reduced responsiveness to exogenous but not endogenous CDNs. These findings confirm and extend previous reports by demonstrating differing impact of allelic variation of STING on the ability to sense and respond to exogenous vs. endogenous CDNs. Finally, the STING-R231H variant mouse represents a useful tool with which to examine the relative contributions of STING sensing of exogenous and endogenous CDNs in the context of bacterial infections and CDN-based cancer immunotherapeutics.

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TMEM173 variants and potential importance to human biology and disease

Cited by 94 publications

References 76 publications

Why isListeria monocytogenessuch a potent inducer of CD8+ T‐cells?

Why isListeria monocytogenessuch a potent inducer of CD8+ T‐cells?

The cGAS‐STING pathway: The role of self‐DNA sensing in inflammatory lung disease

Selective Loss of Responsiveness to Exogenous but Not Endogenous Cyclic-Dinucleotides in Mice Expressing STING-R231H

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