cGAS-activated endothelial cell-T cell cross-talk initiates tertiary lymphoid structure formation
Zhao Ruibo, et al.
Sci Immunol, 2024
The cGAS-STING pathway plays crucial roles in the detection of pathogens that use DNA as a genetic material. In this paper, the authors generated a cGAS conditional knockin mouse model, which leads to activation of STING in vivo. R26-Cre-ERT2;cGasKI/+ mice developed systematic inflammation characterized by a decrease in T cells but an enhancement in T cell activation. They also found that for systematic cGAS or STING overactivation, lung inflammation is the common feature. They then generated Vav-iCre;cGasKI/+ mice to specifically activate cGAS in hematopoietic lineages. They observed that inflammatory cytokines, including TNF-α and IFN-γ as well as the proliferative marker Ki67, were up-regulated at the mRNA level in the lungs. They next revealed the up-regulation of the T cell marker CD3 together with both CD4 and CD8, the macrophage marker F4/80, and the conventional dendritic cell (cDC) marker BATF3, suggesting the presence of the corresponding cell subsets. They further noticed the unique existence of organized lymphoid structures that was characterized as tertiary lymphoid structures (TLSs). They observed three-stage developmental progression in the lungs of Vav-iCre;cGasKI/+ mice. scRNA-seq analysis revealed a decrease in naive CD4+ T cells but an increase in IFN-γ+ CD8+ T cells and TH17 cells as well as CD4+ TFH cells under cGAS hyperactivation. They also revealed that CD8+ T cells expressed the chemokine CXCL13 recruiting B cells, which together advance the formation of TLSs.
DOI: 10.1126/sciimmunol.adk2612
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Histone lactylation-boosted ALKBH3 potentiates tumor progression and diminished promyelocytic leukemia protein nuclear condensates by m1A demethylation of SP100A Gu Xiang, et al.
Nucleic Acids Res. 2024
The precise temporal and spatial regulation of N1-methyladenosine (m1A) RNA modification is essential for epigenome homeostasis. And the mechanism of m1A modification in ocular melanoma tumorigenesis remains unclear. In this paper, the scientists performed genome-wide proteomic analysis and transcriptome screening, uncovering the demethylase ALKBH3 exhibited increased protein expression in ocular melanoma. ALKBH3 presented a significant negative correlation with m1A levels in most melanoma cell lines. Deletion ALKBH3 led to significant attenuation of cell growth and colony formation capacity, suggesting that ALKBH3 serves as a necessary oncogenic factor for malignant proliferation and metastasis of ocular melanoma in vitro. Moreover, the lactate producing enzyme LDHA and LDHB showed significant positive correlation with ALKBH3. Also, CUT&Tag and ChIP-seq of H3K18la analysis demonstrated a robust signal of histone lactylation signal, captured in the promoter region of ALKBH3. Furthermore, multi-omic screening identified nuclear autoantigen speckled protein 100 (SP100) as the downstream candidate of ALKBH3. One of the isoforms of SP100, SP100A, is abundantly expressed in melanoma cell lines. Since SP100A serves as the molecular scaffold within promyelocytic leukemia protein (PML) bodies, they then discovered that ALKBH3-deficient cells exhibited a substantial elevation in PML bodies, consistent with the pivotal role of ALKBH3 in the regulation of SP100A expression. What’s more, they found that YTHDF1 is responsible for recognition of the m1A methylated SP100A transcript, which increases its RNA stability and translational efficacy.DOI: 10.1093/nar/gkad1193
Editor & Reviewer: Yanwen Zhu
