USP15 promotes cGAS activation through deubiquitylation and liquid condensation.

Double-stranded DNA (dsDNA) is recognized as a danger signal by cyclic GMP-AMP synthase (cGAS), which triggers innate immune responses. cGAS activity must be properly regulated to maintain immune homeostasis. However, the mechanism by which cGAS activation is controlled remains to be better understood. In this study, we identified USP15 as a cGAS-interacting partner. USP15 promoted DNA-induced cGAS activation and downstream innate immune responses through a positive feedback mechanism. Specifically, USP15 deubiquitylated cGAS and promoted its activation. In the absence of DNA, USP15 drove cGAS dimerization and liquid condensation through the USP15 intrinsic disordered region (IDR), which prepared cGAS for a rapid response to DNA. Upon DNA stimulation, USP15 was induced to express and boost cGAS activation, functioning as an efficient amplifier in innate immune signal transduction. In summary, the positive role played by USP15-mediated cGAS activation may be a novel regulatory mechanism in the fine-tuning of innate immunity.

Harnessing the therapeutic potential of extracellular vesicles for cancer treatment.

Cancer therapeutic strategies include surgeries, radiotherapy, chemotherapy, targeted therapy and immunotherapies. However, current cancer treatment still faces challenges such as postoperative residuals, postoperative recurrence, chemoradiotherapy resistance and lack of drugs with high specificity, due to the complexity of the cancer environment. Extracellular vesicles (EVs) are lipid-capsuled membrane vesicles secreted from cells, communicating vital messages between cells and regarding function in tumorigenesis and metastasis. Investigation of compositions and functions of EVs may open unprecedented, promising avenues for cancer therapeutics. This review brings new perspectives from both researchers and clinicians in the EV field, emphasizing the ties between basic research and ongoing clinical trials. In sum, our review summarizes the roles EVs play in cancer therapy, ranging from mechanisms to applications in cancer treatment. In particular, it focuses on their therapeutic potential with an eye toward clinical relevance.

Genomic Repeats Categorize Genes with Distinct Functions for Orchestrated Regulation.

Repetitive elements are abundantly distributed in mammalian genomes. Here, we reveal a striking association between repeat subtypes and gene function. SINE, L1, and low-complexity repeats demarcate distinct functional categories of genes and may dictate the time and level of gene expression by providing binding sites for different regulatory proteins. Importantly, imaging and sequencing analysis show that L1 repeats sequester a large set of genes with specialized functions in nucleolus- and lamina-associated inactive domains that are depleted of SINE repeats. In addition, L1 transcripts bind extensively to its DNA in embryonic stem cells (ESCs). Depletion of L1 RNA in ESCs leads to relocation of L1-enriched chromosomal segments from inactive domains to the nuclear interior and de-repression of L1-associated genes. These results demonstrate a role of L1 DNA and RNA in gene silencing and suggest a general theme of genomic repeats in orchestrating the function, regulation, and expression of their host genes.