bims-nenemi 2023-01-22 papers

Issue of 2023‒01‒22
four papers selected by
Marco Tigano
Thomas Jefferson University

Exp Mol Med. 2023 Jan 19.

Site-specific ubiquitination of VDAC1 restricts its oligomerization and mitochondrial DNA release in liver fibrosis.

Ne N Wu, Lifeng Wang, Lu Wang, Xihui Xu, Gary D Lopaschuk, Yingmei Zhang, Jun Ren.

Mitochondrial DNA (mtDNA) released through protein oligomers, such as voltage-dependent anion channel 1 (VDAC1), triggers innate immune activation and thus contributes to liver fibrosis. Here, we investigated the role of Parkin, an important regulator of mitochondria, and its regulation of VDAC1-mediated mtDNA release in liver fibrosis. The circulating mitochondrial DNA (mtDNA) and protein levels of liver Parkin and VDAC1 were upregulated in patients with liver fibrosis. A 4-week CCl4 challenge induced release of mtDNA, activation of STING signaling, a decline in autophagy, and apoptosis in mouse livers, and the knockout of Parkin aggravated these effects. In addition, Parkin reduced mtDNA release and prevented VDAC1 oligomerization in a manner dependent on its E3 activity in hepatocytes. We found that site-specific ubiquitination of VDAC1 at lysine 53 by Parkin interrupted VDAC1 oligomerization and prevented mtDNA release into the cytoplasm under stress. The ubiquitination-defective VDAC1 K53R mutant predominantly formed oligomers that resisted suppression by Parkin. Hepatocytes expressing VDAC1 K53R exhibited mtDNA release and thus activated the STING signaling pathway in hepatic stellate cells, and this effect could not be abolished by Parkin. We propose that the ubiquitination of VDAC1 at a specific site by Parkin confers protection against liver fibrosis by interrupting VDAC1 oligomerization and mtDNA release.

DOI: https://doi.org/10.1038/s12276-022-00923-9

Cell Rep. 2023 Jan 14. pii: S2211-1247(23)00015-3. [Epub ahead of print]42(1): 112004

Downregulation of oxidative stress-mediated glial innate immune response suppresses seizures in a fly epilepsy model.

Krishna M Nukala, Anthony J Lilienthal, Shu Hui Lye, Alexander G Bassuk, Stanislava Chtarbanova, J Robert Manak.

Previous work in our laboratory has shown that mutations in prickle (pk) cause myoclonic-like seizures and ataxia in Drosophila, similar to what is observed in humans carrying mutations in orthologous PRICKLE genes. Here, we show that pk mutant brains show elevated, sustained neuronal cell death that correlates with increasing seizure penetrance, as well as an upregulation of mitochondrial oxidative stress and innate immune response (IIR) genes. Moreover, flies exhibiting more robust seizures show increased levels of IIR-associated target gene expression suggesting they may be linked. Genetic knockdown in glia of either arm of the IIR (Immune Deficiency [Imd] or Toll) leads to a reduction in neuronal death, which in turn suppresses seizure activity, with oxidative stress acting upstream of IIR. These data provide direct genetic evidence that oxidative stress in combination with glial-mediated IIR leads to progression of an epilepsy disorder.

Keywords: CP: Immunology; CP: Neuroscience; epilepsy; glia; innate immunity; neurodegeneration; neuronal cell death; oxidative stress; prickle; seizure disorder

DOI: https://doi.org/10.1016/j.celrep.2023.112004

FASEB J. 2023 Feb;37(2): e22780

The double-stranded RNA-dependent protein kinase PKR negatively regulates the protein expression of IFN-β induced by RIG-I signaling.

Tomoh Matsumiya, Yuko Shiba, Jiangli Ding, Shogo Kawaguchi, Kazuhiko Seya, Tadaatsu Imaizumi.

Retinoic acid-inducible gene-I (RIG-I) is a cytoplasmic RNA sensor that plays an important role in innate immune responses to viral RNAs. Double-stranded RNA (dsRNA)-dependent protein kinase (PKR) is a eukaryotic initiation factor 2α (eIF2α) kinase that is initially involved in the responses of the translational machinery to dsRNA. PKR is also thought to play an essential role in antiviral innate immunity. However, the coordinated mechanisms of RIG-I and PKR that induce the expression of type I interferons (IFNs), essential cytokines involved in antiviral defense, are not completely understood. In this study, we show that PKR negatively participates in the RIG-I-mediated induction of IFN-β expression. Stress granule (SG) formation is crucial to sequester mRNA to prevent aberrant protein synthesis by various stresses. SG formation in response to dsRNA was triggered by a PKR-mediated antiviral stress response. However, IFN-β mRNA was not sequestered in the SGs of dsRNA-treated cells. dsRNA-induced translational silencing was thought to be PKR dependent. However, our results indicated that some proteins, including IFN-β, were clearly translated despite PKR-mediated translational silencing. This study suggests that RIG-I responds mainly to IFN-β expression in cells to which non-self dsRNA is introduced. In addition, PKR negatively regulates IFN-β protein expression induced by RIG-I signaling. This may explain the essential role of PKR in fine-tuning the expression of IFN-β in RIG-I-mediated antiviral immune responses.

Keywords: PKR; RIG-I; antiviral signaling; innate immunity; stress granules

DOI: https://doi.org/10.1096/fj.202201520RR

Nat Commun. 2023 Jan 17. 14(1): 276

DNA damage and somatic mutations in mammalian cells after irradiation with a nail polish dryer.

Maria Zhivagui, Areebah Hoda, Noelia Valenzuela, Yi-Yu Yeh, Jason Dai, Yudou He, Shuvro P Nandi, Burcak Otlu, Bennett Van Houten, Ludmil B Alexandrov.

Ultraviolet A light is commonly emitted by UV-nail polish dryers with recent reports suggesting that long-term use may increase the risk for developing skin cancer. However, no experimental evaluation has been conducted to reveal the effect of radiation emitted by UV-nail polish dryers on mammalian cells. Here, we show that irradiation by a UV-nail polish dryer causes high levels of reactive oxygen species, consistent with 8-oxo-7,8-dihydroguanine damage and mitochondrial dysfunction. Analysis of somatic mutations reveals a dose-dependent increase of C:G>A:T substitutions in irradiated samples with mutagenic patterns similar to mutational signatures previously attributed to reactive oxygen species. In summary, this study demonstrates that radiation emitted by UV-nail polish dryers can both damage DNA and permanently engrave mutations on the genomes of primary mouse embryonic fibroblasts, human foreskin fibroblasts, and human epidermal keratinocytes.

DOI: https://doi.org/10.1038/s41467-023-35876-8