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N6-methyladenosine modification of the 5′ epsilon structure of the HBV pregenome RNA regulates its encapsidation by the viral core protein
Hepatitis B virus (HBV) contains a partially double-stranded DNA genome. During infection, its replication is mediated by reverse transcription (RT) of an RNA intermediate termed pregenomic RNA (pgRNA) within core particles in the cytoplasm. An epsilon structural element located in the 5′ end of the pgRNA primes the RT activity. We have previously identified the N6-methyladenosine (m⁶A)–modified DRACH motif at 1905 to 1909 nucleotides in the epsilon structure that affects myriad functions of the viral life cycle. In this study, we investigated the functional role of m⁶A modification of the 5′ ε (epsilon) structural element of the HBV pgRNA in the nucleocapsid assembly. Using the m⁶A sitemutant in the HBV 5′ epsilon, we present evidence that m⁶A methylation of 5′ epsilon is necessary for its encapsidation. The m⁶A modification of 5′ epsilon increased the efficiency of viral RNA packaging, whereas the m⁶A of 3′ epsilon is dispensable for encapsidation. Similarly, depletion of methyltransferases (METTL3/14) decreased pgRNA and viral DNA levels within the core particles. Furthermore, the m⁶A modification at 5′ epsilon of HBV pgRNA promoted the interaction with core proteins, whereas the 5′ epsilon m⁶A site–mutated pgRNA failed to interact. HBV polymerase interaction with 5′ epsilon was independent of m⁶A modification of 5′ epsilon. This study highlights yet another pivotal role of m⁶A modification in dictating the key events of the HBV life cycle and provides avenues for investigating RNA–protein interactions in various biological processes, including viral RNA genome encapsidation in the context of m⁶A modification.
Journal Article
Runx3 specifies lineage commitment of innate lymphoid cells
The transcriptional control of lineage commitment to various ILC subsets is incompletely understood. Yokoyama and colleagues show that Runx3 is essential for the normal development of ILC1 and ILC3 cells but not ILC2 cells.
Subsets of innate lymphoid cells (ILCs) reside in the mucosa and regulate immune responses to external pathogens. While ILCs can be phenotypically classified into ILC1, ILC2 and ILC3 subsets, the transcriptional control of commitment to each ILC lineage is incompletely understood. Here we report that the transcription factor Runx3 was essential for the normal development of ILC1 and ILC3 cells but not of ILC2 cells. Runx3 controlled the survival of ILC1 cells but not of ILC3 cells. Runx3 was required for expression of the transcription factor RORγt and its downstream target, the transcription factor AHR, in ILC3 cells. The absence of Runx3 in ILCs exacerbated infection with
Citrobacter rodentium
. Therefore, our data establish Runx3 as a key transcription factor in the lineage-specific differentiation of ILC1 and ILC3 cells.
Journal Article
Effects of cellular membranes and the precore protein on hepatitis B virus core particle assembly and DNA replication
Hepatitis B virus (HBV) is an important human pathogen that chronically infects 254 million people in the world. This virus contains a core particle, which plays an important role in the transport and replication of the viral DNA genome. The major protein constituent of this particle is the viral core protein. In this report, we examined how the subcellular compartments and the related precore protein might affect the core particle structure and viral DNA replication. We found that the subcellular localizations could affect the core particle assembly, and membranes and the precore protein could regulate HBV DNA replication. We also found that the inhibition of autophagic degradation increased the precore protein level, suggesting a role of autophagy in the regulation of precore protein activities. These findings provided important information for further understanding the HBV life cycle, which will aid in the development of novel drugs for the treatment of HBV patients.
Journal Article
Novel biomarkers: the RUNX family as prognostic predictors in colorectal cancer
While biomarkers have been shown to enhance the prognosis of patients with colorectal cancer (CRC) compared to conventional treatments, there is a pressing need to discover novel biomarkers that can assist in assessing the prognostic impact of immunotherapy and in formulating individualized treatment plans. The RUNX family, consisting of RUNX1, RUNX2, and RUNX3, has been recognized as crucial regulators in developmental processes, with dysregulation of these genes also being implicated in tumorigenesis and cancer progression. In our present study, we demonstrated a crucial regulatory role of RUNX in CD8 + T and CD103 + CD8 + T cell-mediated anti-tumor response within the tumor microenvironment (TME) of human CRC. Specifically, RUNXs were significantly differentially expressed between tumor and normal tissues in CRC. Patients with a greater proportion of infiltrating CD8 + RUNX1 + , CD103 + CD8 + RUNX1 + , CD8 + RUNX2 + , CD103 + CD8 + RUNX2 + , CD8 + RUNX3 + , or CD103 + CD8 + RUNX3 + T cells demonstrated improved outcomes compared to those with lower proportions. Additionally, the proportions of infiltrating CD8 + RUNX1 + T and CD8 + RUNX3 + T cells may serve as valuable prognostic predictors for CRC patients, independent of other clinicopathological factors. Moreover, further bioinformatic analysis conducted utilizing the TISIDB and TIMER platforms demonstrated significant associations between the members of the RUNX family and immune-infiltrating cells, specifically diverse subpopulations of CD8 + TILs. Our study of human colorectal cancer tissue microarray (TMA) also revealed positive and statistically significant correlations between the expressions of RUNX1, RUNX2, and RUNX3 in both CD8 + T cells and CD103 + CD8 + T cells. Our study comprehensively revealed the varied expressions and prognostic importance of the RUNX family in human colorectal cancer tissues. It underscored their potential as vital biomarkers for prognostic evaluation in colorectal cancer patients and as promising targets for immunotherapy in treating this disease.
Journal Article
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\"Simple text and full-color photographs describe the hottest places on the planet\"-- Provided by publisher.
Book
Runx/Cbfβ complexes protect group 2 innate lymphoid cells from exhausted-like hyporesponsiveness during allergic airway inflammation
Group 2 innate lymphoid cells (ILC2s) have tissue-resident competence and contribute to the pathogenesis of allergic diseases. However, the mechanisms regulating prolonged ILC2-mediated T
H
2 cytokine production under chronic inflammatory conditions are unclear. Here we show that, at homeostasis, Runx deficiency induces excessive ILC2 activation due to overly active GATA-3 functions. By contrast, during allergic inflammation, the absence of Runx impairs the ability of ILC2s to proliferate and produce effector T
H
2 cytokines and chemokines. Instead, functional deletion of Runx induces the expression of exhaustion markers, such as IL-10 and TIGIT, on ILC2s. Finally, these ‘exhausted-like’ ILC2s are unable to induce type 2 immune responses to repeated allergen exposures. Thus, Runx confers competence for sustained ILC2 activity at the mucosa, and contributes to allergic pathogenesis.
Group 2 innate lymphoid cells (ILC2) are important mediators for allergy, but how ILC2 are regulated under chronic inflammation is still unclear. Here the authors show that Runx transcription factors, which normally suppresses ILC2 activation at steady state, help promote ILC2 activation and type 2 cytokine production in lung allergy mouse models.
Journal Article