Cell insight最新文献

Type 2 immunity in the lung protects against pathogenic infection and facilitates tissue repair, but its dysregulation may lead to severe human diseases. Notably, cannabis usage for medical or recreational purposes has increased globally. However, the potential impact of the cannabinoid signal on lung immunity is incompletely understood. Here, we report that cannabinoid receptor 2 (CB2) is highly expressed in group 2 innate lymphoid cells (ILC2s) of mouse and human lung tissues. Of importance, the CB2 signal enhances the IL-33-elicited immune response of ILC2s. In addition, the chemogenetic manipulation of inhibitory G proteins (Gi) downstream of CB2 produces a similarly promotive effect. Conversely, the genetic deletion of CB2 mitigates the IL-33-elicited type 2 immunity in the lung. Also, such ablation of the CB2 signal ameliorates papain-induced tissue inflammation. Together, these results have elucidated a critical aspect of the CB2 signal in lung immunity, implicating its potential involvement in pulmonary diseases.

Over the years, much attention has been drawn to antibiotic resistance bacteria, but drug inefficacy caused by a subgroup of special phenotypic variants – persisters – has been largely neglected in both scientific and clinical field. Interestingly, this subgroup of phenotypic variants displayed their power of withstanding sufficient antibiotics exposure in a mechanism different from antibiotic resistance. In this review, we summarized the clinical importance of bacterial persisters, the evolutionary link between resistance, tolerance, and persistence, redundant mechanisms of persister formation as well as methods of studying persister cells. In the light of our recent findings of membrane-less organelle aggresome and its important roles in regulating bacterial dormancy depth, we propose an alternative approach for anti-persister therapy. That is, to force a persister into a deeper dormancy state to become a VBNC (viable but non-culturable) cell that is incapable of regrowth. We hope to provide the latest insights on persister studies and call upon more research interest into this field.

Mitochondrial DNA (mtDNA) encodes proteins and RNAs that are essential for mitochondrial function and cellular homeostasis, and participates in important processes of cellular bioenergetics and metabolism. Alterations in mtDNA are associated with various diseases, especially cancers, and are considered as biomarkers for some types of tumors. Moreover, mtDNA alterations have been found to affect the proliferation, progression and metastasis of cancer cells, as well as their interactions with the immune system and the tumor microenvironment (TME). The important role of mtDNA in cancer development makes it a significant target for cancer treatment. In recent years, many novel therapeutic methods targeting mtDNA have emerged. In this study, we first discussed how cancerogenesis is triggered by mtDNA mutations, including alterations in gene copy number, aberrant gene expression and epigenetic modifications. Then, we described in detail the mechanisms underlying the interactions between mtDNA and the extramitochondrial environment, which are crucial for understanding the efficacy and safety of mtDNA-targeted therapy. Next, we provided a comprehensive overview of the recent progress in cancer therapy strategies that target mtDNA. We classified them into two categories based on their mechanisms of action: indirect and direct targeting strategies. Indirect targeting strategies aimed to induce mtDNA damage and dysfunction by modulating pathways that are involved in mtDNA stability and integrity, while direct targeting strategies utilized molecules that can selectively bind to or cleave mtDNA to achieve the therapeutic efficacy. This study highlights the importance of mtDNA-targeted therapy in cancer treatment, and will provide insights for future research and development of targeted drugs and therapeutic strategies.

R-loops are regulators of many cellular processes and are threats to genome integrity. Therefore, understanding the mechanisms underlying the regulation of R-loops is important. Inspired by the findings on RNase H1-mediated R-loop degradation or accumulation, we focused our interest on the regulation of RNase H1 expression. In the present study, we report that G9a positively regulates RNase H1 expression to boost R-loop degradation. CHCHD2 acts as a repressive transcription factor that inhibits the expression of RNase H1 to promote R-loop accumulation. Sirt1 interacts with CHCHD2 and deacetylates it, which functions as a corepressor that suppresses the expression of downstream target gene RNase H1. We also found that G9a methylated the promoter of RNase H1, inhibiting the binding of CHCHD2 and Sirt1. In contrast, when G9a was knocked down, recruitment of CHCHD2 and Sirt1 to the RNase H1 promoter increased, which co-inhibited RNase H1 transcription. Furthermore, knockdown of Sirt1 led to binding of G9a to the RNase H1 promoter. In summary, we demonstrated that G9a regulates RNase H1 expression to maintain the steady-state balance of R-loops by suppressing the recruitment of CHCHD2/Sirt1 corepressors to the target gene promoter.

Eukaryotic viruses are obligate intracellular parasites that rely on the host cell machinery to carry out their replication cycle. This complex process involves a series of steps, starting with virus entry, followed by genome replication, and ending with virion assembly and release. Negative strand RNA and some DNA viruses have evolved to alter the organization of the host cell interior to create a specialized environment for genome replication, known as IBs, which are precisely orchestrated to ensure efficient viral replication. The biogenesis of IBs requires the cooperation of both viral and host factors. These structures serve multiple functions during infection, including sequestering viral nucleic acids and proteins from innate immune responses, increasing the local concentration of viral and host factors, and spatially coordinating consecutive replication cycle steps. While ultrastructural and functional studies have improved our understanding of IBs, much remains to be learned about the precise mechanisms of IB formation and function. This review aims to summarize the current understanding of how IBs are formed, describe the morphology of these structures, and highlight the mechanism of their functions. Given that the formation of IBs involves complex interactions between the virus and the host cell, the role of both viral and cellular organelles in this process is also discussed.

Histidine methylation serves as an intriguing strategy to introduce altered traits of target proteins, including metal ion chelation, histidine-based catalysis, molecular assembly, and translation regulation. As a newly identified histidine methyltransferase, METTL9 catalyzes N1-methylation of protein substrates containing the “His-x-His” motif (HxH, x denotes small side chain residue). Here our structural and biochemical studies revealed that METTL9 specifically methylates the second histidine of the “HxH” motif, while exploiting the first one as a recognition signature. We observed an intimate engagement between METTL9 and a pentapeptide motif, where the small “x” residue is embedded and confined within the substrate pocket. Upon complex formation, the N3 atom of histidine imidazole ring is stabilized by an aspartate residue such that the N1 atom is presented to S-adenosylmethionine for methylation. Moreover, METTL9 displayed a feature in preferred consecutive and “C-to-N” directional methylation of tandem “HxH” repeats that exist in many METTL9 substrates. Collectively, our work illustrates the molecular design of METTL9 in N1-specific methylation of the broadly existing “HxH” motifs, highlighting its importance in histidine methylation biology.