Histone demethylase LSD1 promotes RIG-I poly-ubiquitination and anti-viral gene expression

Hu, Qi-Xin; Wang, Hui-Yi; Jiang, Lu; Wang, Chenyu; Ju, Lingao; Zhu, Yuan; Zhong, Bo; Wu, Min; Wang, Zhen; Li, Lianyun

doi:10.1371/journal.ppat.1009918

Cited by 4 publications

(2 citation statements)

References 59 publications

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“…For example, histone H3K36me3 methylase SETD2 has been shown to be critical in the response to HBV [ 16 ]. H3K4 demethylase LSD1 regulates K63-linked polyubiquitination of RIG-I and the subsequent anti-viral response and IFNB1 expression [ 17 ]. Besides the classic innate immunity pathway, epigenetics is also involved in other processes related to viral infection.…”

Section: Introductionmentioning

confidence: 99%

The roles of nuclear orphan receptor NR2F6 in anti-viral innate immunity

Yang,

Wang,

Long

et al. 2024

PLoS Pathog

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Proper transcription regulation by key transcription factors, such as IRF3, is critical for anti-viral defense. Dynamics of enhancer activity play important roles in many biological processes, and epigenomic analysis is used to determine the involved enhancers and transcription factors. To determine new transcription factors in anti-DNA-virus response, we have performed H3K27ac ChIP-Seq and identified three transcription factors, NR2F6, MEF2D and MAFF, in promoting HSV-1 replication. NR2F6 promotes HSV-1 replication and gene expression in vitro and in vivo, but not dependent on cGAS/STING pathway. NR2F6 binds to the promoter of MAP3K5 and activates AP-1/c-Jun pathway, which is critical for DNA virus replication. On the other hand, NR2F6 is transcriptionally repressed by c-Jun and forms a negative feedback loop. Meanwhile, cGAS/STING innate immunity signaling represses NR2F6 through STAT3. Taken together, we have identified new transcription factors and revealed the underlying mechanisms involved in the network between DNA viruses and host cells.

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Section: Introductionmentioning

confidence: 99%

The roles of nuclear orphan receptor NR2F6 in anti-viral innate immunity

Yang,

Wang,

Long

et al. 2024

PLoS Pathog

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“…However, the antiviral properties of LSD1 against RNA viruses have only recently been described. In particular, LSD1 overexpression impairs Vesicular Stomatitis Virus (VSV) replication by promoting retinoic acid-inducible gene I (RIG-I) poly-ubiquitination [11] and restricts Influenza A Virus (IAV) infection after interferon stimulation [12]. The above-mentioned studies highlight the diverse role of LSD1 in viral propagation and infection, which largely depends on the particular viral life cycle.…”

Section: Introductionmentioning

confidence: 99%

The Epigenetic Controller Lysine-Specific Demethylase 1 (LSD1) Regulates the Outcome of Hepatitis C Viral Infection

Papadopoulou,

Petroulia,

Karamichali

et al. 2023

Cells

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Hepatitis C virus (HCV) alters gene expression epigenetically to rearrange the cellular microenvironment in a beneficial way for its life cycle. The host epigenetic changes induced by HCV lead to metabolic dysfunction and malignant transformation. Lysine-specific demethylase 1 (LSD1) is an epigenetic controller of critical cellular functions that are essential for HCV propagation. We investigated the putative role of LSD1 in the establishment of HCV infection using genetic engineering and pharmacological inhibition to alter endogenous LSD1 levels. We demonstrated for the first time that HCV replication was inhibited in LSD1-overexpressing cells, while specific HCV proteins differentially fine-tuned endogenous LSD1 expression levels. Electroporation of the full-length HCV genome and subgenomic replicons in LSD1 overexpression enhanced translation and partially restored HCV replication, suggesting that HCV might be inhibited by LSD1 during the early steps of infection. Conversely, the inhibition of LSD1, followed by HCV infection in vitro, increased viral replication. LSD1 was shown to participate in an intriguing antiviral mechanism, where it activates endolysosomal interferon-induced transmembrane protein 3 (IFITM3) via demethylation, leading endocytosed HCV virions to degradation. Our study proposes that HCV-mediated LSD1 oscillations over countless viral life cycles throughout chronic HCV infection may promote epigenetic changes related to HCV-induced hepatocarcinogenesis.

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ARIH1 inhibits influenza A virus replication and facilitates RIG-I dependent immune signaling by interacting with SQSTM1/p62

Wang

Chen

et al. 2023

Virol J

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Background Multiple host factors are involved in modulating type I interferon expression induced by viruses; however, the mechanism is not fully elucidated. Influenza A virus infection causes severe respiratory symptoms and triggers a series of signaling cascades and host innate immune responses, including interferon production. The co-IP/MS technology was used to screen several antiviral factors in the early stage. Among these factors, ariadne-1 homolog (ARIH1) caught our attention. Methods Western blot assay was performed to detect the level of proteins and software ImageJ was used to analyze the band intensities. Polymerase activity assay was conducted to evaluate the polymerase activity of influenza A virus. Tissue culture infective dose (TCID50) assay was performed to measure influenza A virus titers, and quantitative RT-PCR assay was applied to test the mRNA level of IFN-β, ISG56, and CXCL10. Luciferase reporter assay was used to confirm the target of ARIH1 in RIG-I signaling. Immunoprecipitation assay was performed to detect the interaction and the ubiquitination of the proteins. All data were analyzed by biostatistical methods and presented as means ± standard deviation from three independent experiments. Statistical significance was determined using two-tailed student’s t test. A P value of less than 0.05 was considered statistically significant, and a P value of less than 0.01 was considered highly significant (ns, P ≥ 0.05; *, P < 0.05; and **, P < 0.01). Results We found that ARIH1, a member of E3 ubiquitin ligases, enhanced cellular antiviral responses. Subsequent study showed that ARIH1 was up-regulated during influenza A virus infection. Further analysis showed that ARIH1 enhanced IFN-β and downstream gene expression by affecting the degradation of RIG-I through the SQSTM1/p62 signaling pathway. Conclusion This newly revealed mechanism shows that cellular response increases of ARIH1 and promotes IFN-β expression to boost host survival during viral infection.

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Histone demethylase LSD1 promotes RIG-I poly-ubiquitination and anti-viral gene expression

Cited by 4 publications

References 59 publications

The roles of nuclear orphan receptor NR2F6 in anti-viral innate immunity

The roles of nuclear orphan receptor NR2F6 in anti-viral innate immunity

The Epigenetic Controller Lysine-Specific Demethylase 1 (LSD1) Regulates the Outcome of Hepatitis C Viral Infection

ARIH1 inhibits influenza A virus replication and facilitates RIG-I dependent immune signaling by interacting with SQSTM1/p62

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