The RNA-binding protein ZC3H11A interacts with the nuclear poly(A)-binding protein PABPN1 and alters polyadenylation of viral transcripts

Kases, Katharina; Schubert, Erik; Hajikhezri, Zamaneh; Larsson, Mårten; Devi, Priya; Darweesh, Mahmoud; Andersson, Leif; Akusjärvi, Göran; Punga, Tanel; Younis, Shady

doi:10.1016/j.jbc.2023.104959

Cited by 3 publications

(2 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Proteins were considered for further analysis if they exhibited at least two-thirds valid data points within each experimental condition. We addressed missing values using the deterministic minimal value (MinDet) imputation method, 32 which aids in mitigating the bias that can arise from non-random data absence. ImageJ (v1.54) was used for the quantification of western blot and analysis of immunofluorescent images.…”

Section: Methodsmentioning

confidence: 99%

De novo HDAC3variants leading to epigenetic machinery dysfunction are associated with a neurodevelopmental disorder

Yoon,

Lim,

Seo

et al. 2024

Preprint

View full text Add to dashboard Cite

Histone deacetylase 3 (HDAC3) is a crucial epigenetic modulator essential for brain development. Although its dysfunction is increasingly recognized in various neurodevelopmental disorders, there have been no reports of human diseases related to HDAC3 dysfunction in Online Mendelian Inheritance in Man (OMIM). This study establishes a novel link between heterozygous de novo variants in HDAC3 and a distinct neurodevelopmental syndrome, characterized by intellectual disability, developmental delays, and other variable manifestations such as musculoskeletal anomalies and congenital heart defects. In a cohort of six individuals, we identified de novo missense HDAC3 variants (D93N, A110T, P201S, L266S, G267S, and R359C), all located in evolutionarily conserved sites. Using trio exome sequencing and extensive phenotypic analysis, we correlated these genetic alterations with the observed clinical spectrum. Our investigations using HDAC assays and western blot analyses identified reduced deacetylation activity in the L266S and G267S variants, positioned near the enzymatic pocket. Additionally, proteomic analysis employing co-immunoprecipitation revealed that disrupted interactions with key multi-protein complexes, particularly CoREST and NCoR in the A110T variant, suggesting a critical pathogenic mechanism. Moreover, immunofluorescence analysis revealed diminished fluorescence intensity (nuclear to cytoplasmic ratio) in the A110T, G267S, and R359C variants, indicating impaired nuclear localization. This study highlights that de novo HDAC3 variants are associated with a novel neurodevelopmental syndrome, emphasizing the importance of histone deacetylase activity, multi-protein complex interactions, and nuclear localization for normal cellular function of HDAC3. These insights open new possibilities for understanding the molecular mechanisms of this uncharacterized neurodevelopmental disorder and may inform future therapeutic approaches.

show abstract

Section: Methodsmentioning

confidence: 99%

De novo HDAC3variants leading to epigenetic machinery dysfunction are associated with a neurodevelopmental disorder

Yoon,

Lim,

Seo

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…For instance, zinc finger antiviral protein (ZAP), which is a host antiviral factor, binds to the CpG island of HIV-1 and directs its RNA degradation by interacting with cofactor KHNYN [47]; ZAP also binds to the enriched CG regions of SARS-CoV-2 RNA sequences to direct its degradation [48,49]. Kases et al [50] demonstrated that ZC3H11A interacts with human adenovirus type 5 (HAdV-5) capsid mRNA, using zinc finger motifs (ZFM) to bind to the viral RNA in a PABPN1-dependent manner, whereas ZC3H11A with ZFM mutants showed reduced protein-RNA interaction [50]. Girardi et al [51] have provided an extended review of the influence of RBPs on host-virus interaction [51].…”

Section: Process Of Viral Rna Degradationmentioning

confidence: 99%

A Genetic Circuit Design for Targeted Viral RNA Degradation

Bello,

Popoola,

Okpuzor

et al. 2023

Bioengineering

View full text Add to dashboard Cite

Advances in synthetic biology have led to the design of biological parts that can be assembled in different ways to perform specific functions. For example, genetic circuits can be designed to execute specific therapeutic functions, including gene therapy or targeted detection and the destruction of invading viruses. Viral infections are difficult to manage through drug treatment. Due to their high mutation rates and their ability to hijack the host’s ribosomes to make viral proteins, very few therapeutic options are available. One approach to addressing this problem is to disrupt the process of converting viral RNA into proteins, thereby disrupting the mechanism for assembling new viral particles that could infect other cells. This can be done by ensuring precise control over the abundance of viral RNA (vRNA) inside host cells by designing biological circuits to target vRNA for degradation. RNA-binding proteins (RBPs) have become important biological devices in regulating RNA processing. Incorporating naturally upregulated RBPs into a gene circuit could be advantageous because such a circuit could mimic the natural pathway for RNA degradation. This review highlights the process of viral RNA degradation and different approaches to designing genetic circuits. We also provide a customizable template for designing genetic circuits that utilize RBPs as transcription activators for viral RNA degradation, with the overall goal of taking advantage of the natural functions of RBPs in host cells to activate targeted viral RNA degradation.

show abstract

Complex regulation of mitochondrial signaling by human adenovirus minor capsid protein VI

Schubert,

Mun,

Larsson

et al. 2024

J Virol

View full text Add to dashboard Cite

The controlled release of mitochondrial content into the cytosol has emerged as one of the key steps in mitochondrial signaling. In particular, the release of mitochondrial DNA (mtDNA) into the cytosol has been shown to activate interferon beta (IFN-β) gene expression to execute the innate immune response. In this report, we show that human adenovirus type 5 (HAdV-C5) infection induces the release of mtDNA into the cytosol. The release of mtDNA is mediated by the viral minor capsid protein VI (pVI), which localizes to mitochondria. The presence of the mitochondrial membrane proteins Bak and Bax are needed for the mtDNA release, whereas the viral E1B-19K protein blocked pVI-mediated mtDNA release. Surprisingly, the pVI-mediated mtDNA release did not increase but inhibited the IFN-β gene expression. Notably, the pVI expression caused mitochondrial leakage of the HSP60 protein. The latter prevented specific phosphorylation of the interferon regulatory factor 3 (IRF3) needed for IFN-β gene expression. Overall, we assign a new mitochondria and IFN-β signaling-modulating function to the HAdV-C5 minor capsid protein VI. IMPORTANCE Human adenoviruses (HAdVs) are common pathogens causing various self-limiting diseases, including conjunctivitis and the common cold. HAdVs need to interfere with multiple cellular signaling pathways during the infection to gain control over the host cell. In this study, we identified human adenovirus type 5 (HAdV-C5) minor capsid protein VI as a factor modulating mitochondrial membrane integrity and mitochondrial signaling. We show that pVI-altered mitochondrial signaling impedes the cell’s innate immune response, which may benefit HAdV growth. Overall, our study provides new detailed insights into the HAdV-mitochondria interactions and signaling. This knowledge is helpful when developing new anti-viral treatments against pathogenic HAdV infections and improving HAdV-based therapeutics.

show abstract

The RNA-binding protein ZC3H11A interacts with the nuclear poly(A)-binding protein PABPN1 and alters polyadenylation of viral transcripts

Cited by 3 publications

References 61 publications

De novo HDAC3variants leading to epigenetic machinery dysfunction are associated with a neurodevelopmental disorder

De novo HDAC3variants leading to epigenetic machinery dysfunction are associated with a neurodevelopmental disorder

A Genetic Circuit Design for Targeted Viral RNA Degradation

Complex regulation of mitochondrial signaling by human adenovirus minor capsid protein VI

Contact Info

Product

Resources

About