Positive Role of Promyelocytic Leukemia Protein in Type I Interferon Response and Its Regulation by Human Cytomegalovirus

Type I interferon signaling contributes to the development of innate and adaptive immune responses to either viruses, fungi, or bacteria. However, amplitude and timing of the interferon response is of utmost importance for preventing an underwhelming outcome, or tissue damage. While several pathogens evolved strategies for disturbing the quality of interferon signaling, there is growing evidence that this pathway can be regulated by several members of the Nod-like receptor (NLR) family, although the precise mechanism for most of these remains elusive. NLRs consist of a family of about 20 proteins in mammals, which are capable of sensing microbial products as well as endogenous signals related to tissue injury. Here we provide an overview of our current understanding of the function of those NLRs in type I interferon responses with a focus on viral infections. We discuss how NLR-mediated type I interferon regulation can influence the development of auto-immunity and the immune response to infection.

Download Full-text

Human Cytomegalovirus UL23 Attenuates Signal Transducer and Activator of Transcription 1 Phosphorylation and Type I Interferon Response

Frontiers in Microbiology ◽

10.3389/fmicb.2021.692515 ◽

2021 ◽

Vol 12 ◽

Author(s):

Linyuan Feng ◽

Wanwei Li ◽

Xingyuan Wu ◽

Xiaotian Li ◽

Xiaoping Yang ◽

...

Keyword(s):

Human Cytomegalovirus ◽

Type I Interferon ◽

Signal Transduction Pathway ◽

Interferon Response ◽

Type I ◽

Signal Transducer ◽

Tyrosine Kinase 2 ◽

Disease Occurrence ◽

Key Factor ◽

Determining Factor

Human cytomegalovirus (HCMV), the human beta-herpesvirus, can cause severe syndromes among both immunocompromised adult patients and newborns. Type I interferon (IFN-I) exerts an important effect to resist infections caused by viruses such as HCMV, while IFN evasion may serve as a key determining factor for viral dissemination and disease occurrence within hosts. In this study, UL23, a tegument protein of HCMV, was confirmed to be a key factor for negatively regulating the type I IFN immune response. A detailed analysis indicated that the viral UL23 protein increases the IFN-I antiviral resistance during HCMV infections. Furthermore, UL23 was shown to significantly reduce the levels of IFN-stimulated genes (ISGs) and promoter activity of IFN-I-stimulated response element. Mechanically, UL23 was discovered to impair the signal transducer and activator of transcription 1 (STAT1) phosphorylation, although it was not found to affect phosphorylation and expression of STAT2, Janus activated kinase 1, or tyrosine kinase 2, which are associated with IFN-I signal transduction pathway. Additionally, a significantly reduced nuclear expression of STAT1 but not of IFN regulatory factor 9 or STAT2 was observed. Findings of this study indicate that HCMV UL23 is a viral antagonist that acts against the cellular innate immunity and reveal a possible novel effect of UL23 on IFN-I signaling.

Download Full-text

Drosophila STING protein has a role in lipid metabolism

10.1101/2021.02.04.429825 ◽

2021 ◽

Author(s):

Katarina Akhmetova ◽

Maxim Balasov ◽

Igor Chesnokov

Keyword(s):

Lipid Metabolism ◽

Fatty Acid Synthase ◽

Type I Interferon ◽

Interferon Response ◽

Type I ◽

Acetyl Coa Carboxylase ◽

Direct Role ◽

Lipid Metabolism Genes ◽

And Oxidative Stress

ABSTRACTStimulator of interferon genes (STING) plays an important role in innate immunity by controlling type I interferon response against invaded pathogens. In this work we describe a direct but previously unknown role of STING in lipid metabolism in Drosophila. Flies with STING deletion are sensitive to starvation and oxidative stress, have reduced lipid storage and downregulated expression of lipid metabolism genes. We found that Drosophila STING interacts with lipid synthesizing enzymes acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). ACC and FAS also interact with each other, indicating that all three proteins may be components of a large multi-enzyme complex. The deletion of Drosophila STING leads to disturbed ACC localization and decreased FAS enzyme activity. Together, our results demonstrate a direct role of STING in lipid metabolism in Drosophila.

Download Full-text

Drosophila STING protein has a role in lipid metabolism

eLife ◽

10.7554/elife.67358 ◽

2021 ◽

Vol 10 ◽

Author(s):

Katarina Akhmetova ◽

Maxim Balasov ◽

Igor Chesnokov

Keyword(s):

Lipid Metabolism ◽

Fatty Acid Synthase ◽

Type I Interferon ◽

Interferon Response ◽

Type I ◽

Enzyme Complex ◽

Acetyl Coa Carboxylase ◽

Lipid Metabolism Genes ◽

And Oxidative Stress

Stimulator of interferon genes (STING) plays an important role in innate immunity by controlling type I interferon response against invaded pathogens. In this work, we describe a previously unknown role of STING in lipid metabolism in Drosophila. Flies with STING deletion are sensitive to starvation and oxidative stress, have reduced lipid storage, and downregulated expression of lipid metabolism genes. We found that Drosophila STING interacts with lipid synthesizing enzymes acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN). ACC and FASN also interact with each other, indicating that all three proteins may be components of a large multi-enzyme complex. The deletion of Drosophila STING leads to disturbed ACC localization and decreased FASN enzyme activity. Together, our results demonstrate a previously undescribed role of STING in lipid metabolism in Drosophila.

Download Full-text