Enhanced ISGylation reduces respiratory distress followingFrancisella novicidainfection DOI Creative Commons
Ellen M. Upton, Emma K. Luhmann, Yifeng Zhang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 20, 2023

Abstract The Interferon-Stimulated Gene 15 (ISG15) is a ubiquitin-like protein induced by viral and bacterial infection. ISG15 covalently modifies host pathogenic proteins in process called ISGylation. Yet, the consequences of ISGylation on fate function remain to be determined. Here we sought assess whether would protective following pneumonia caused Francisella novicida. We found that infection with F. novicida induces both vitro macrophages vivo lung, liver, spleen mice infected intranasally. Surprisingly, do not affect burden lung , but model enhanced ( usp18 C61A/C61A ) have decreased respiratory distress relative Isg15 -/- animals. In order understand mechanism which underlies this phenotype, mapped ISGylome novicida- mouse lungs using label-free quantitative mass spectrometry identified enrichment involved innate immune response cytosolic nucleotide signaling. validated sterile alpha motif HD-containing 1 (SAMHD1) via immunoprecipitation. SAMHD1 depletes dinucleotide stores critical for retroviral replication it unknown how its activity could Structure-function analysis indicates modification sites prevent dimerization therefore abrogate function. Accordingly, deletion fibroblasts reduces load. Taken together, unchecked plays role through improved Thus, inhibiting USP18 may promising therapeutic strategy pneumonia. Author summary tularensis pathogen responsible disease tularemia, can result severe if as few ten bacteria are inhaled. Our cells many ways managing infections, including production designed fight off foreign pathogens. One produced interferon-stimulated gene (ISG15). molecule, meaning chemically attached other proteins. When bound changes stability, interacting partners, or target termed show Francisella. led less symptoms. To better protects from ISG15-modified mass-spectrometry-based proteomics. targets control signaling pathways which, when deleted ISGylation, leads clearance. Together, pneumonia, indicating targeting pathway prove beneficial diseases.

Language: Английский

SAMHD1 dysfunction induces IL-34 expression via NF-κB p65 in neuronal SH-SY5Y cells DOI
Ling Zhang, Wenjing Wang, Ting Chen

et al.

Molecular Immunology, Journal Year: 2024, Volume and Issue: 168, P. 1 - 9

Published: Feb. 17, 2024

Language: Английский

Citations

4
Phenazine biosynthesis-like domain-containing protein (PBLD) and Cedrelone promote antiviral immune response by activating NF-ĸB DOI Creative Commons
Peili Hou, Hongchao Zhu,

Fengyun Chu

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 8, 2025

Phenazine biosynthesis-like domain-containing protein (PBLD) and Cedrelone have been identified as tumor suppressors. However, their roles in virus infection remain unclear. Here, we demonstrate that PBLD upregulates the type I interferon (IFN-I) response through activating NF-kappaB (NF-κB) signaling pathway to resist viral cells mice. Mechanistically, activates NF-κB during via blocking tripartite motif containing 21 (TRIM21)-mediated phosphorylated inhibitory kappa B kinase beta (IKKβ) degradation. Furthermore, show inhibits replication by increasing expression subsequently NF-κB-mediated IFN-I response. therapeutic potential of lies its ability enhance antiviral immunity primary macrophages promote survival reduce lung tissue damage HSV-1-infected mice a PBLD-dependent manner. Consequently, our findings provide combination model targets for drug therapy, potentially paving way development broad-spectrum agents.

Language: Английский

Citations

0
SAMHD1 enhances HIV-1-induced apoptosis in monocytic cells via the mitochondrial pathway DOI Creative Commons
Hua Yang, Pak‐Hin Hinson Cheung, Li Wu

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 10, 2025

SUMMARY Sterile alpha motif (SAM) and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) inhibits HIV-1 replication in non-dividing cells by reducing the intracellular dNTP pool. SAMHD1 enhances spontaneous apoptosis cells, but its effects on HIV-1-induced underlying mechanisms remain unknown. Here we uncover a new mechanism which monocytic through mitochondrial pathway. We found that endogenous levels induced infection dividing THP-1 cells. Mechanistically, expression decreases membrane potential promotes cytochrome c release thereby enhancing apoptotic SAMHD1-enhanced is associated with increased of pro-apoptotic BCL-2-interacting killer (BIK) further demonstrated BIK contributes to during infection. Overall, our results reveal an unappreciated regulatory via pathway

Language: Английский

Citations

0
dNTP depletion and beyond: the multifaceted nature of SAMHD1-mediated viral restriction DOI Creative Commons
Pak‐Hin Hinson Cheung, Hua Yang, Li Wu

et al.

Journal of Virology, Journal Year: 2025, Volume and Issue: unknown

Published: April 25, 2025

ABSTRACT SAMHD1 is a dNTPase of mammalian cells. In 2011, was found to be host restriction factor against retroviruses through dNTP reduction. Recent research provides evidence that the antiviral mechanisms cannot explained solely by its activity. Instead, versatility SAMHD1-mediated various viruses suggests extend beyond depletion. This explains multifaceted and broad functions play significant role in innate immunity.

Language: Английский

Citations

0
SAMHD1 deficiency enhances macrophage-mediated clearance of Salmonella Typhimurium via NF-κB activation in zebrafish DOI Creative Commons

Alicia Martínez-López,

Sylwia D. Tyrkalska, Francisco J. Martínez-Morcillo

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: April 25, 2025

Mutations in the gene encoding protein containing sterile alpha motif and HD domain (SAMHD1) have been implicated occurrence of type I interferonopathies. SAMHD1 is also involved blocking replication retroviruses certain DNA viruses by reducing intracellular amount deoxynucleotide triphosphates (dNTPs). It has suggested that negatively regulates interferon (IFN) inflammatory responses to viral infections; however, functions mechanisms modulating innate immunity are still under study. In our laboratory, we generated Samhd1-deficient zebrafish larvae using CRISPR-Cas9 studied its role activation nuclear factor kappa B (NF-κB) induction IFN (IFN-I). was shown Samhd1 deficiency results overactivation IFN-I response, assayed as increased transcript levels Interferon Stimulated Genes (ISGs), but only if were stimulated with suboptimal doses IFN-I. However, showed robust spontaneous NF-κB, which led larval resistance Salmonella enterica serovar Typhimurium (STM) infection. Genetic experiments further NF-κB macrophages mediated against STM. These findings highlight evolutionary conserved negative regulation response vertebrates reveal, for first time, a critical clear bacterial

Language: Английский

Citations

0
Identification and Characterization of Immune-Associated MicroRNAs in Silver Carp (Hypophthalmichthys molitrix) Responding to Aeromonas veronii and LPS Stimulation DOI Creative Commons
Meng Liu, Huan Tang, Kun Gao

et al.

Animals, Journal Year: 2024, Volume and Issue: 14(2), P. 285 - 285

Published: Jan. 17, 2024

The ubiquitous Gram-negative bacterial pathogen Aeromonas veronii (A. veronii) can easily cause inflammatory reactions in aquatic organisms, resulting high mortality and huge economic losses. MicroRNAs (miRNAs) participate immune regulation have certain conserved properties. MiRNAs are involved the responses of a variety teleost fish infected with bacteria, whereas there is no related report silver carp (Hypophthalmichthys molitrix). Therefore, we identified expression profiles miRNA stimulated by A. LPS. Among them, quantity differentially expressed miRNAs (DEmiRNAs) obtained challenge group was 73 90 (LPS). GO enrichment analysis KEGG pathways shown that predicted target genes mainly associated lipid metabolism response carp. This indicates possibility play role regulating immune-related pathways. In addition, total eight DEmiRNAs validated accuracy sequencing result via quantitative real-time PCR (qRT-PCR). Finally, selected head kidney macrophage cells (HKCs) as model proved miR-30b-5p regulate HKCs. study lays foundation for exploring during pathogenic infection. it provides reference future development non-coding RNA antibacterial drugs.

Language: Английский

Citations

2
Nuclear Overexpression of SAMHD1 Induces M Phase Stalling in Hepatoma Cells and Suppresses HCC Progression by Interacting with the Cohesin Complex DOI Creative Commons
Juntang Shao, Wei Wang, Shiyu Li

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 16, 2024

Abstract Emerging evidence suggests that the sterile alpha‐motif (SAM) and histidine‐aspartate (HD) domain‐containing protein 1 (SAMHD1) is implicated in various cancers, including hepatocellular carcinoma (HCC). However, its precise role tumor cells underlying mechanisms remain unclear. This study aimed to investigate expression patterns, prognostic values, functional of SAMHD1 HCC progression. We constructed liver tissue microarrays using paired paratumor specimens from 187 patients with primary HCC. Our findings indicate nuclear levels are increased tumors compared tissues. Moreover, decline advanced stages, higher staining correlating favorable outcomes. Hepatocyte‐specific knockout mice, generated by crossing fl/fl mice Alb‐cre showed accelerated progression a diethylnitrosamine (DEN)‐induced model. In hepatoma cell lines, overexpression inhibited proliferation stalling mitosis, independent deoxynucleotide triphosphohydrolase (dNTPase) function. Mechanistically, interacts cohesin complex nucleus, enhancing sister chromatid cohesion during division, which delays metaphase suggest plays critical slowing regulating highlighting potential as therapeutic target manipulating dynamics.

Language: Английский

Citations

0
Enhanced ISGylation reduces respiratory distress followingFrancisella novicidainfection DOI Creative Commons
Ellen M. Upton, Emma K. Luhmann, Yifeng Zhang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 20, 2023

Abstract The Interferon-Stimulated Gene 15 (ISG15) is a ubiquitin-like protein induced by viral and bacterial infection. ISG15 covalently modifies host pathogenic proteins in process called ISGylation. Yet, the consequences of ISGylation on fate function remain to be determined. Here we sought assess whether would protective following pneumonia caused Francisella novicida. We found that infection with F. novicida induces both vitro macrophages vivo lung, liver, spleen mice infected intranasally. Surprisingly, do not affect burden lung , but model enhanced ( usp18 C61A/C61A ) have decreased respiratory distress relative Isg15 -/- animals. In order understand mechanism which underlies this phenotype, mapped ISGylome novicida- mouse lungs using label-free quantitative mass spectrometry identified enrichment involved innate immune response cytosolic nucleotide signaling. validated sterile alpha motif HD-containing 1 (SAMHD1) via immunoprecipitation. SAMHD1 depletes dinucleotide stores critical for retroviral replication it unknown how its activity could Structure-function analysis indicates modification sites prevent dimerization therefore abrogate function. Accordingly, deletion fibroblasts reduces load. Taken together, unchecked plays role through improved Thus, inhibiting USP18 may promising therapeutic strategy pneumonia. Author summary tularensis pathogen responsible disease tularemia, can result severe if as few ten bacteria are inhaled. Our cells many ways managing infections, including production designed fight off foreign pathogens. One produced interferon-stimulated gene (ISG15). molecule, meaning chemically attached other proteins. When bound changes stability, interacting partners, or target termed show Francisella. led less symptoms. To better protects from ISG15-modified mass-spectrometry-based proteomics. targets control signaling pathways which, when deleted ISGylation, leads clearance. Together, pneumonia, indicating targeting pathway prove beneficial diseases.

Language: Английский

Citations

0