EMBO Reports最新文献

Cytokinesis physically separates daughter cells at the end of cell division. This step is particularly challenging for epithelial cells, which are connected to their neighbors and to the extracellular matrix by transmembrane protein complexes. To systematically evaluate the impact of the cell adhesion machinery on epithelial cytokinesis efficiency, we performed an RNAi-based modifier screen in the Drosophila follicular epithelium. Strikingly, this unveiled adhesion molecules and transmembrane receptors that facilitate cytokinesis completion. Among these is Dystroglycan, which connects the extracellular matrix to the cytoskeleton via Dystrophin. Live imaging revealed that Dystrophin and Dystroglycan become enriched in the ingressing membrane, below the cytokinetic ring, during and after ring constriction. Using multiple alleles, including Dystrophin isoform-specific mutants, we show that Dystrophin/Dystroglycan localization is linked with unanticipated roles in regulating cytokinetic ring contraction and in preventing membrane regression during the abscission period. Altogether, we provide evidence that, rather than opposing cytokinesis completion, the machinery involved in cell-cell and cell-matrix interactions has also evolved functions to ensure cytokinesis efficiency in epithelial tissues.

Retinoic acid (RA) signaling is a master regulator of vertebrate development with crucial roles in body axis orientation and tissue differentiation, including in the reproductive system. However, a mechanistic understanding of how RA signaling governs cell lineage identity is often missing. Here, leveraging prostate organoid technology, we show that RA signaling orchestrates the commitment of adult mouse prostate progenitors to glandular identity, epithelial barrier integrity, and specification of prostatic lumen. RA-dependent RARγ activation promotes the expression of Foxa1, which synergizes with the androgen pathway for luminal expansion, cytoarchitecture and function. FOXA1 mutations are common in prostate and breast cancers, though their pathogenic mechanism is incompletely understood. Combining functional genetics with structural modeling of FOXA1 folding and chromatin binding analyses, we discover that FOXA1^F254E255 is a loss-of-function mutation compromising its transcriptional function and luminal fate commitment of prostate progenitors. Overall, we define RA as an instructive signal for glandular identity in adult prostate progenitors. Importantly, we identify cancer-associated FOXA1 indels affecting residue F254 as loss-of-function mutations promoting dedifferentiation of adult prostate progenitors.

Cholesterol metabolism is associated with innate immune responses; however, the underlying mechanism remains unclear. Here, we perform chemical screening to isolate small molecules influencing RIG-I activity, a cytoplasmic viral RNA sensor. We find that statins, which inhibit cholesterol synthesis, dramatically enhance RIG-I-dependent antiviral responses in specific cell types. Since statins exhibit pleiotropic effects on type I interferon (IFN) responses, we further focus on their effects on RIG-I signaling. The restriction of cholesterol synthesis induces expression of noncanonical type I IFNs, such as IFN-ω, in an SREBP1 transcription factor-dependent manner. This pathway subsequently enhances RIG-I-mediated signaling following viral infection. Administration of statins augments RIG-I-dependent cytokine expression in the lungs of mice. Conversely, a mouse obesity model shows a diminished RIG-I response. Single-cell transcriptome analyses reveal a subset of alveolar macrophages that increase RIG-I expression in response to inhibited cholesterol synthesis in vivo. This study reveals SREBP1-mediated noncanonical type I IFN expression, linking cholesterol metabolism and RIG-I signaling.

Interferon-gamma (IFNγ) is a pleiotropic cytokine produced by natural killer (NK) cells during the early infection response. IFNγ expression is tightly regulated to mount sterilizing immunity while preventing tissue pathology. Several post-transcriptional effectors dampen IFNγ expression through IFNG mRNA degradation. In this study, we identify mRNA splicing as a positive regulator of IFNγ production. While treatment with the combination of IL-12 and IL-2 causes synergistic induction of IFNG mRNA and protein, defying transcription-translation kinetics, we observe that NK cells treated with IL-12 alone transcribe IFNG with introns intact. When NK cells are treated with both IL-2 and IL-12, IFNG transcript is spliced to form mature mRNA with a concomitant increase in IFNγ protein. We find that IL-2-mediated intron splicing occurs independently of nascent transcription but relies upon NF-κB signaling. We propose that while IL-12 transcriptionally induces IFNG mRNA, IL-2 signaling stabilizes IFNG mRNA by splicing detained introns, allowing for rapid IFNγ protein production. This study uncovers a novel role for cytokine-induced splicing in regulating IFNγ through a mechanism potentially applicable to other inflammatory mediators.

Triple-negative breast cancer (TNBC) disproportionately affects younger Black women, who show more aggressive phenotypes and poorer outcomes than women of other racial identities. While the impact of socioenvironmental inequities within and beyond health systems is well documented, the genetic influence in TNBC-associated racial disparities remains elusive. Here, we report that cancer-free breast tissue from Black women expresses TRIM37 at a significantly higher level relative to White women. A reporter-based screen for regulatory variants identifies a non-coding risk variant rs57141087 in the 5' gene upstream region of the TRIM37 locus with enhancer activity. Mechanistically, rs57141087 increases enhancer-promoter interactions through NRF1, resulting in stronger TRIM37 promoter activity. Phenotypically, high TRIM37 levels drive neoplastic transformations in immortalized breast epithelial cells. Finally, context-dependent TRIM37 expression reveals that early-stage TRIM37 levels affect the initiation and trajectory of breast cancer progression. Together, our results indicate a genotype-informed association of oncogenic TRIM37 with TNBC risk in Black women and implicate TRIM37 as a predictive biomarker to better identify patients at risk of aggressive TNBC.

Transient receptor potential vanilloid 1 (TRPV1) is a capsaicin-sensitive ion channel implicated in pain sensation. While TRPV1 potentiation in hyperalgesia development has been extensively investigated, its functional decline during pain relief remains largely unexplored. Here, by molecular, electrophysiological and in vivo evidence, we reveal that S-palmitoylation fine-tunes TRPV1 function by promoting its degradation via the lysosome pathway thereby facilitating inflammatory pain relief. The palmitoyl acyltransferase ZDHHC4 is identified to physically interact with TRPV1 and to catalyze S-palmitoylation at the cysteine residues C157, C362, C390, and C715 of the channel. Furthermore, we show that TRPV1 palmitoylation is counterbalanced by the depalmitoylase acyl-protein thioesterase 1 (APT1), thereby reinstating pain sensation. These findings provide important mechanistic insights into the relief phase of inflammatory pain.

Folic acid (FA) is well known to prevent neural tube defects (NTDs), but we do not know why many human NTD cases still remain refractory to FA supplementation. Here, we investigate how the DNA demethylase TET1 interacts with maternal FA status to regulate mouse embryonic brain development. We determined that cranial NTDs display higher penetrance in non-inbred than in inbred Tet1^-/- embryos and are resistant to FA supplementation across strains. Maternal diets that are either too rich or deficient in FA are linked to an increased incidence of cranial deformities in wild type and Tet1^+/- offspring and to altered DNA hypermethylation in Tet1^-/- embryos, primarily at neurodevelopmental loci. Excess FA in Tet1^-/- embryos results in phospholipid metabolite loss and reduced expression of multiple membrane solute carriers, including a FA transporter gene that exhibits increased promoter DNA methylation and thereby mimics FA deficiency. Moreover, FA deficiency reveals that Tet1 haploinsufficiency can contribute to DNA hypermethylation and susceptibility to NTDs. Overall, our study suggests that epigenetic dysregulation may underlie NTD development despite FA supplementation.

The Retriever complex recycles a wide range of transmembrane proteins from endosomes to the plasma membrane. The cargo adapter protein SNX17 has been implicated in recruiting the Retriever complex to endosomal membranes, yet the details of this interaction have remained elusive. Through biophysical and structural model-guided mutagenesis studies with recombinant proteins and liposomes, we have gained a deeper understanding of this process. Here, we demonstrate a direct interaction between SNX17 and Retriever, specifically between the C-terminal region of SNX17 and the interface of the Retriever subunits VPS35L and VPS26C. This interaction is enhanced upon the binding of SNX17 to its cargo in solution, due to the disruption of an intramolecular autoinhibitory interaction between the C-terminal region of SNX17 and the cargo binding pocket. In addition, SNX17 binding to membranes containing phosphatidylinositol-3-phosphate also promotes Retriever recruitment in a cargo-independent manner. Therefore, this work provides evidence of the dual activation mechanisms by which SNX17 modulates Retriever recruitment to the proximity of cargo and membranes, offering significant insights into the regulatory mechanisms of protein recycling at endosomes.