scholarly journals The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Hale Tunbak ◽  
Rocio Enriquez-Gasca ◽  
Christopher H. C. Tie ◽  
Poppy A. Gould ◽  
Petra Mlcochova ◽  
...  
Keyword(s):  
Dna Damage ◽  
Type I Interferon ◽  
Type I ◽  
Human Cell Lines ◽  
Interferon Signaling ◽  
Interferon Stimulated Genes ◽  
Primary Fibroblasts ◽  
Gene Regulatory ◽  
Epigenetic Repression ◽  
Specific Line

Abstract The Human Silencing Hub (HUSH) complex is necessary for epigenetic repression of LINE-1 elements. We show that HUSH-depletion in human cell lines and primary fibroblasts leads to induction of interferon-stimulated genes (ISGs) through JAK/STAT signaling. This effect is mainly attributed to MDA5 and RIG-I sensing of double-stranded RNAs (dsRNAs). This coincides with upregulation of primate-conserved LINE-1s, as well as increased expression of full-length hominid-specific LINE-1s that produce bidirectional RNAs, which may form dsRNA. Notably, LTRs nearby ISGs are derepressed likely rendering these genes more responsive to interferon. LINE-1 shRNAs can abrogate the HUSH-dependent response, while overexpression of an engineered LINE-1 construct activates interferon signaling. Finally, we show that the HUSH component, MPP8 is frequently downregulated in diverse cancers and that its depletion leads to DNA damage. These results suggest that LINE-1s may drive physiological or autoinflammatory responses through dsRNA sensing and gene-regulatory roles and are controlled by the HUSH complex.

Abstract B05: Induction of DNA damage in high-grade serous carcinoma induces type I interferon signaling

2020 ◽  
Author(s):  
Danielle E. Bolland ◽  
Yuning Hao ◽  
Yee Sun Tan ◽  
Jake Reske ◽  
Lijun Tan ◽  
...  
Keyword(s):  
Dna Damage ◽  
Type I Interferon ◽  
Serous Carcinoma ◽  
Type I ◽  
High Grade ◽  
Interferon Signaling

scholarly journals Induction of DNA Damage in Ovarian Cancer Induces Type I Interferon Signaling

2018 ◽  
Vol 32 (S1) ◽  
Author(s):  
Danielle E. Bolland ◽  
Yee Sun Tan ◽  
Yuning Hao ◽  
Kari E. Hacker ◽  
Lijun Tan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Type I Interferon ◽  
Type I ◽  
Interferon Signaling

scholarly journals SARS-CoV-2 disrupts proximal elements in the JAK-STAT pathway

2021 ◽  
Author(s):  
Da-Yuan Chen ◽  
Nazimuddin Khan ◽  
Brianna J. Close ◽  
Raghuveera K. Goel ◽  
Benjamin Blum ◽  
...  
Keyword(s):  
Cell Lines ◽  
Human Cell ◽  
Type I Interferon ◽  
Cell Types ◽  
Janus Kinase ◽  
Type I ◽  
Human Cell Lines ◽  
Interferon Signaling ◽  
Interferon Receptor ◽  
Stat Pathway

SARS-CoV-2 can infect multiple organs, including lung, intestine, kidney, heart, liver, and brain. The molecular details of how the virus navigates through diverse cellular environments and establishes replication are poorly defined. Here, we generated a panel of phenotypically diverse, SARS-CoV-2-infectable human cell lines representing different body organs and performed longitudinal survey of cellular proteins and pathways broadly affected by the virus. This revealed universal inhibition of interferon signaling across cell types following SARS-CoV-2 infection. We performed systematic analyses of the JAK-STAT pathway in a broad range of cellular systems, including immortalized cells and primary-like cardiomyocytes, and found that SARS-CoV-2 targeted the proximal pathway components, including Janus kinase 1 (JAK1), tyrosine kinase 2 (Tyk2), and the interferon receptor subunit 1 (IFNAR1), resulting in cellular desensitization to type I IFN. Detailed mechanistic investigation of IFNAR1 showed that the protein underwent ubiquitination upon SARS-CoV-2 infection. Furthermore, chemical Inhibition of JAK kinases enhanced infection of stem cell-derived cultures, indicating that the virus benefits from inhibiting the JAK-STAT pathway. These findings suggest that the suppression of interferon signaling is a mechanism widely used by the virus to evade antiviral innate immunity, and that targeting the viral mediators of immune evasion may help block virus replication in patients with COVID-19. IMPORTANCE SARS-CoV-2 can infect various organs in the human body, but the molecular interface between the virus and these organs remains unexplored. In this study, we generated a panel of highly infectable human cell lines originating from various body organs and employed these cells to identify cellular processes commonly or distinctly disrupted by SARS-CoV-2 in different cell types. One among the universally impaired processes was interferon signaling. Systematic analysis of this pathway in diverse culture systems showed that SARS-CoV-2 targets the proximal JAK-STAT pathway components, destabilizes the type I interferon receptor though ubiquitination, and consequently renders the infected cells resistant to type I interferon. These findings illuminate how SARS-CoV-2 can continue to propagate in different tissues even in the presence of a disseminated innate immune response.

scholarly journals Proteinase 2Apro Is Essential for Enterovirus Replication in Type I Interferon-Treated Cells

2009 ◽  
Vol 83 (9) ◽  
pp. 4412-4422 ◽  
Author(s):  
Juliet M. Morrison ◽  
Vincent R. Racaniello
Keyword(s):  
Type I Interferon ◽  
Encephalomyocarditis Virus ◽  
Type I ◽  
Interferon Signaling ◽  
Interferon Stimulated Genes ◽  
Interferon Pathway ◽  
Antiviral Activities ◽  
Enterovirus Type ◽  
Vesicular Stomatitis

ABSTRACT The Picornaviridae family comprises a diverse group of small RNA viruses that cause a variety of human and animal diseases. Some of these viruses are known to induce cleavage of components of the innate immune system and to inhibit steps in the interferon pathway that lead to the production of type I interferon. There has been no study of the effect of picornaviral infection on the events that occur after interferons have been produced. To determine whether members of the Enterovirus genus can antagonize the antiviral activity of interferon-stimulated genes (ISGs), we pretreated cells with alpha interferon (IFN-α) and then infected the cells with poliovirus type 1, 2, or 3; enterovirus type 70; or human rhinovirus type 16. We found that these viruses were able to replicate in IFN-α-pretreated cells but that replication of vesicular stomatitis virus, a Rhabdovirus, and encephalomyocarditis virus (EMCV), a picornavirus of the Cardiovirus genus, was completely inhibited. Although EMCV is sensitive to IFN-α, coinfection of cells with poliovirus and EMCV leads to EMCV replication in IFN-α-pretreated cells. The enteroviral 2A proteinase (2Apro) is essential for replication in cells pretreated with interferon, because amino acid changes in this protein render poliovirus sensitive to IFN-α. The addition of the poliovirus 2Apro gene to the EMCV genome allowed EMCV to replicate in IFN-α-pretreated cells. These results support an inhibitory role for 2Apro in the most downstream event in interferon signaling, the antiviral activities of ISGs.

scholarly journals Positive natural selection in primate genes of the type I interferon response

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Elena N. Judd ◽  
Alison R. Gilchrist ◽  
Nicholas R. Meyerson ◽  
Sara L. Sawyer
Keyword(s):  
Natural Selection ◽  
Positive Selection ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Sequence Alignments ◽  
Multiple Sequence ◽  
Multiple Sequence Alignments ◽  
Interferon Stimulated Genes ◽  
Interferon Induction

Abstract Background The Type I interferon response is an important first-line defense against viruses. In turn, viruses antagonize (i.e., degrade, mis-localize, etc.) many proteins in interferon pathways. Thus, hosts and viruses are locked in an evolutionary arms race for dominance of the Type I interferon pathway. As a result, many genes in interferon pathways have experienced positive natural selection in favor of new allelic forms that can better recognize viruses or escape viral antagonists. Here, we performed a holistic analysis of selective pressures acting on genes in the Type I interferon family. We initially hypothesized that the genes responsible for inducing the production of interferon would be antagonized more heavily by viruses than genes that are turned on as a result of interferon. Our logic was that viruses would have greater effect if they worked upstream of the production of interferon molecules because, once interferon is produced, hundreds of interferon-stimulated proteins would activate and the virus would need to counteract them one-by-one. Results We curated multiple sequence alignments of primate orthologs for 131 genes active in interferon production and signaling (herein, “induction” genes), 100 interferon-stimulated genes, and 100 randomly chosen genes. We analyzed each multiple sequence alignment for the signatures of recurrent positive selection. Counter to our hypothesis, we found the interferon-stimulated genes, and not interferon induction genes, are evolving significantly more rapidly than a random set of genes. Interferon induction genes evolve in a way that is indistinguishable from a matched set of random genes (22% and 18% of genes bear signatures of positive selection, respectively). In contrast, interferon-stimulated genes evolve differently, with 33% of genes evolving under positive selection and containing a significantly higher fraction of codons that have experienced selection for recurrent replacement of the encoded amino acid. Conclusion Viruses may antagonize individual products of the interferon response more often than trying to neutralize the system altogether.

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