scholarly journals Nuclear cGAS: sequestration and beyond

2021 ◽  
Author(s):  
Juli Bai ◽  
Feng Liu

AbstractThe cyclic GMP-AMP (cGAMP) synthase (cGAS) has been identified as a cytosolic double stranded DNA sensor that plays a pivotal role in the type I interferon and inflammation responses via the STING-dependent signaling pathway. In the past several years, a growing body of evidence has revealed that cGAS is also localized in the nucleus where it is associated with distinct nuclear substructures such as nucleosomes, DNA replication forks, the double-stranded breaks, and centromeres, suggesting that cGAS may have other functions in addition to its role in DNA sensing. However, while the innate immune function of cGAS is well established, the non-canonical nuclear function of cGAS remains poorly understood. Here, we review our current understanding of the complex nature of nuclear cGAS and point to open questions on the novel roles and the mechanisms of action of this protein as a key regulator of cell nuclear function, beyond its well-established role in dsDNA sensing and innate immune response.

1998 ◽  
Vol 26 (1) ◽  
pp. 53-70 ◽  
Author(s):  
William A. Davis

Thomas hardy was at work on his last novel, Jude the Obscure, when two of the best-known New Woman novels of the 1890s, Sarah Grand's The Heavenly Twins and George Gissing's The Odd Women, appeared in 1893. Hardy read The Heavenly Twins, or at least parts of it, in May 1893 and noted its criticism of the “constant cultivation of the [female] animal instincts” (i.e., the marital and maternal instincts) in his notebook (qtd. in Literary Notebooks 2:57). Hardy met Sarah Grand later in the spring and praised her to his friend Florence Henniker as a writer who had “decided to offend her friends (so she told me) — & now that they are all alienated she can write boldly, & get listened to” (Collected Letters 2:33). Hardy was also at this time looking into the popular short-story collection Keynotes (1893) by George Egerton (Mary Chavelita Clairmonte), from which he copied a passage concerning man's inability to appreciate “the problems of [woman's] complex nature” (qtd. in Literary Notebooks 2:60). Hardy's interest in George Egerton continued for several years. He wrote to Florence Henniker in January 1894 and reported that he had “found out no more about Mrs. Clairmont [sic]”; Sue Bridehead at this same time was still “very nebulous” (Collected Letters 2:47). Two years later, Hardy had found the author of Keynotes and finished his novel: he wrote to Mrs. Clairmonte in late December 1895, two months after the publication of Jude the Obscure, and commented on their shared interest in the Sue characters “type”: “I have been intending for years to draw Sue, & it is extraordinary that a type of woman, comparatively common & getting commoner, should have escaped fiction so long” (Collected Letters 2:102). Hardy's comment suggests that Sue's origins were, at least in part, real New Women, and that he had been following the New Woman phenomenon for several years. Hardy had completed work on Jude in the spring of 1895 while simultaneously reading another New Woman novel, the best-selling and controversial The Woman Who Did (1895) by Grant Allen. Hardy wrote to Allen in February 1895 to thank Allen for sending a copy of the novel and to express his praise for the book, which he had read “from cover to cover.” Hardy added that it “was curious to find how exactly [Allen] had anticipated my view” (Collected Letters 2:68).


2020 ◽  
Author(s):  
Silian Chen ◽  
Miao Rong ◽  
Yun Lv ◽  
Deyu Zhu ◽  
Ye Xiang

AbstractCyclic GMP-AMP synthase (cGAS) is a double-stranded DNA (dsDNA) sensor that functions in the innate immune system. Upon binding dsDNA in the cytoplasm, cGAS and dsDNA form phase-separated aggregates in which cGAS catalyzes synthesis of 2’3’-cyclic GMP-AMP that subsequently triggers a STING-dependent, type I IFN response. Here, we showed that cytoplasmic RNAs, especially tRNAs, regulate cGAS activity. We discovered that RNAs did not activate cGAS but rather promoted phase separation in vitro. In cells, cGAS colocalized with RNAs and formed phase-separated granules even in the absence of cytoplasmic dsDNA. An Opti-prep gradient analysis of cell lysates showed that the endogenous cGAS was associated with cytoplasmic RNAs in an aggregative form. Further in vitro assays showed that RNAs compete for binding of cGAS with dsDNA and inhibit cGAS activity when the dsDNA concentration is high and promote the formation of phase separations and enhance cGAS activity when the dsDNA concentration is low. Thus, cytoplasmic RNAs regulate cGAS activity by interfering with formation of cGAS-containing aggregates.


2021 ◽  
Vol 22 (6) ◽  
pp. 3090
Author(s):  
Toshimasa Shimizu ◽  
Hideki Nakamura ◽  
Atsushi Kawakami

Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by chronic inflammation of the salivary and lacrimal glands and extra-glandular lesions. Adaptive immune response including T- and B-cell activation contributes to the development of SS. However, its pathogenesis has not yet been elucidated. In addition, several patients with SS present with the type I interferon (IFN) signature, which is the upregulation of the IFN-stimulated genes induced by type I IFN. Thus, innate immune responses including type I IFN activity are associated with SS pathogenesis. Recent studies have revealed the presence of activation pattern recognition receptors (PRRs) including Toll-like receptors, RNA sensor retinoic acid-inducible gene I and melanoma differentiation-associated gene 5, and inflammasomes in infiltrating and epithelial cells of the salivary glands among patients with SS. In addition, the activation of PRRs via the downstream pathway such as the type I IFN signature and nuclear factor kappa B can directly cause organ inflammation, and it is correlated with the activation of adaptive immune responses. Therefore, this study assessed the role of the innate immune signal pathway in the development of inflammation and immune abnormalities in SS.


Author(s):  
Zaheer Ahmed ◽  
Alberto Cassese ◽  
Gerard van Breukelen ◽  
Jan Schepers

AbstractWe present a novel method, REMAXINT, that captures the gist of two-way interaction in row by column (i.e., two-mode) data, with one observation per cell. REMAXINT is a probabilistic two-mode clustering model that yields two-mode partitions with maximal interaction between row and column clusters. For estimation of the parameters of REMAXINT, we maximize a conditional classification likelihood in which the random row (or column) main effects are conditioned out. For testing the null hypothesis of no interaction between row and column clusters, we propose a $$max-F$$ m a x - F test statistic and discuss its properties. We develop a Monte Carlo approach to obtain its sampling distribution under the null hypothesis. We evaluate the performance of the method through simulation studies. Specifically, for selected values of data size and (true) numbers of clusters, we obtain critical values of the $$max-F$$ m a x - F statistic, determine empirical Type I error rate of the proposed inferential procedure and study its power to reject the null hypothesis. Next, we show that the novel method is useful in a variety of applications by presenting two empirical case studies and end with some concluding remarks.


2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Zhi Zong ◽  
Yujun Wei ◽  
Jiang Ren ◽  
Long Zhang ◽  
Fangfang Zhou

AbstractThe outbreak of the novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as a serious public health concern. Patients with cancer have been disproportionately affected by this pandemic. Increasing evidence has documented that patients with malignancies are highly susceptible to severe infections and mortality from COVID-19. Recent studies have also elucidated the molecular relationship between the two diseases, which may not only help optimize cancer care during the pandemic but also expand the treatment for COVID-19. In this review, we highlight the clinical and molecular similarities between cancer and COVID-19 and summarize the four major signaling pathways at the intersection of COVID-19 and cancer, namely, cytokine, type I interferon (IFN-I), androgen receptor (AR), and immune checkpoint signaling. In addition, we discuss the advantages and disadvantages of repurposing anticancer treatment for the treatment of COVID-19.


Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1298
Author(s):  
Raina K. Plowright ◽  
Peter J. Hudson

Pandemics are a consequence of a series of processes that span scales from viral biology at 10−9 m to global transmission at 106 m. The pathogen passes from one host species to another through a sequence of events that starts with an infected reservoir host and entails interspecific contact, innate immune responses, receptor protein structure within the potential host, and the global spread of the novel pathogen through the naive host population. Each event presents a potential barrier to the onward passage of the virus and should be characterized with an integrated transdisciplinary approach. Epidemic control is based on the prevention of exposure, infection, and disease. However, the ultimate pandemic prevention is prevention of the spillover event itself. Here, we focus on the potential for preventing the spillover of henipaviruses, a group of viruses derived from bats that frequently cross species barriers, incur high human mortality, and are transmitted among humans via stuttering chains. We outline the transdisciplinary approach needed to prevent the spillover process and, therefore, future pandemics.


2021 ◽  
Vol 1 (1) ◽  
pp. 49-59
Author(s):  
Selvakumar Subbian

The Coronavirus Disease-2019 (COVID-19) pandemic, caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has claimed 1.2 million people globally since December 2019. Although the host factors underpinning COVID-19 pathology are not fully understood, type I interferon (IFN-I) response is considered crucial for SARS-CoV-2 pathogenesis. Perturbations in IFN-I signaling and associated interferon-inducible genes (ISG) are among the primary disease severity indicators in COVID-19. Consequently, IFN-I therapy, either alone or in- combination with existing antiviral or anti-inflammatory drugs, is tested in many ongoing clinical trials to reduce COVID-19 mortality. Since signaling by the IFN-I family of molecules regulates host immune response to other infectious and non-infectious diseases, any imbalance in this family of cytokines would impact the clinical outcome of COVID-19, as well as other co-existing diseases. Therefore, it is imperative to evaluate the beneficial-versus-detrimental effects of IFN-I immunotherapy for COVID-19 patients with divergent disease severity and other co-existing conditions. This review article summarizes the role of IFN-I signaling in infectious and non-infectious diseases of humans. It highlights the precautionary measures to be considered before administering IFN-I to COVID-19 patients having other co-existing disorders. Finally, suggestions are proposed to improve IFN-I immunotherapy to COVID-19.


Pathogens ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 675
Author(s):  
Samira Elmanfi ◽  
Mustafa Yilmaz ◽  
Wilson W. S. Ong ◽  
Kofi S. Yeboah ◽  
Herman O. Sintim ◽  
...  

Host cells can recognize cytosolic double-stranded DNAs and endogenous second messengers as cyclic dinucleotides—including c-di-GMP, c-di-AMP, and cGAMP—of invading microbes via the critical and essential innate immune signaling adaptor molecule known as STING. This recognition activates the innate immune system and leads to the production of Type I interferons and proinflammatory cytokines. In this review, we (1) focus on the possible role of bacterial cyclic dinucleotides and the STING/TBK1/IRF3 pathway in the pathogenesis of periodontal disease and the regulation of periodontal immune response, and (2) review and discuss activators and inhibitors of the STING pathway as immune response regulators and their potential utility in the treatment of periodontitis. PubMed/Medline, Scopus, and Web of Science were searched with the terms “STING”, “TBK 1”, “IRF3”, and “cGAS”—alone, or together with “periodontitis”. Current studies produced evidence for using STING-pathway-targeting molecules as part of anticancer therapy, and as vaccine adjuvants against microbial infections; however, the role of the STING/TBK1/IRF3 pathway in periodontal disease pathogenesis is still undiscovered. Understanding the stimulation of the innate immune response by cyclic dinucleotides opens a new approach to host modulation therapies in periodontology.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lukas Wettstein ◽  
Tatjana Weil ◽  
Carina Conzelmann ◽  
Janis A. Müller ◽  
Rüdiger Groß ◽  
...  

AbstractSARS-CoV-2 is a respiratory pathogen and primarily infects the airway epithelium. As our knowledge about innate immune factors of the respiratory tract against SARS-CoV-2 is limited, we generated and screened a peptide/protein library derived from bronchoalveolar lavage for inhibitors of SARS-CoV-2 spike-driven entry. Analysis of antiviral fractions revealed the presence of α1-antitrypsin (α1AT), a highly abundant circulating serine protease inhibitor. Here, we report that α1AT inhibits SARS-CoV-2 entry at physiological concentrations and suppresses viral replication in cell lines and primary cells including human airway epithelial cultures. We further demonstrate that α1AT binds and inactivates the serine protease TMPRSS2, which enzymatically primes the SARS-CoV-2 spike protein for membrane fusion. Thus, the acute phase protein α1AT is an inhibitor of TMPRSS2 and SARS-CoV-2 entry, and may play an important role in the innate immune defense against the novel coronavirus. Our findings suggest that repurposing of α1AT-containing drugs has prospects for the therapy of COVID-19.


Sign in / Sign up

Export Citation Format

Share Document