EMBO Reports最新文献

Overcoming lysogenization defect (OLD) proteins are diverse ATPase-nucleases functioning in antiphage defense in bacteria. However, the role of these proteins in archaea is currently unknown. We describe a new class of archaeal OLD family ATPases and show that they are apparently not involved in antiviral defense but play an essential role in cell cycle progression. The gene for an OLD family enzyme in Saccharolobus islandicus REY15A, named here Cran1 (Cell cycle-related ATPase and nickase 1), cannot be deleted and exhibits cyclic expression patterns at transcriptional and translational levels, with peak expression during the transition from M-G1 to S phase. Cran1 overexpression causes significant growth retardation, cell size enlargement, and increased cellular DNA content. Cran1 displays potent nickase and ATPase activities in vitro, with the nickase activity dependent on the presence of the ATPase domain. Notably, Cran1 copurifies with chromatin-associated proteins, such as Cren7 and a histone deacetylase homolog, suggesting its involvement in chromatin-related activities. Collectively, our results suggest that Cran1 plays an important role in cell cycle progression, revealing a novel function of OLD family proteins.

Adipocytes play essential roles in lipid metabolism and energy homeostasis, with regional differences affecting their functions and disease susceptibility. However, the mechanisms underlying this regional heterogeneity remain unclear. Here we demonstrate that the Bithorax Complex (BX-C) genes, specifically abdominal A (abd-A) and Abdominal B (Abd-B), define regional differences in Drosophila larval adipocytes. Abdominal adipocytes, expressing abd-A and Abd-B exhibit unique characteristics compared to thoracic adipocytes, with active Wnt/Wingless signaling further amplifying these regional differences. Depleting abd-A and Abd-B in adipocytes delays larval-pupal transition, causes pupal lethality, and attenuates the expression of Wnt/Wg target genes, thereby dampening Wnt signaling-induced lipid mobilization. Additionally, Wnt signaling enhances the transcription of abd-A and Abd-B, establishing a feedforward loop that reinforces the interplay between Wnt signaling and BX-C genes. These findings reveal how the cell-autonomous expression of BX-C genes defines adipocyte heterogeneity, a process further modulated by Wnt signaling in Drosophila larvae.

The choice between somatic and germline fates is essential for species survival. This choice occurs in embryonic epiblast cells, as these cells are competent for both somatic and germline differentiation. The transcription factor OTX2 regulates this process, as Otx2-null epiblast-like cells (EpiLCs) form primordial germ cell-like cells (PGCLCs) with enhanced efficiency. Yet, how OTX2 achieves this function is not fully characterised. Here we show that OTX2 controls chromatin accessibility at specific chromatin loci to enable somatic differentiation. CUT&RUN for OTX2 and ATAC-seq in wild-type and Otx2-null embryonic stem cells and EpiLCs identifies regions where OTX2 binds and opens chromatin. Enforced OTX2 expression maintains accessibility at these regions and also induces opening of ~4000 somatic-associated regions in cells differentiating in the presence of PGC-inducing cytokines. Once cells have acquired germline identity, these additional regions no longer respond to OTX2 and remain closed. Our results indicate that OTX2 works in cells with dual competence for somatic and germline differentiation to increase accessibility of somatic regulatory regions and induce the somatic fate at the expense of the germline.

Eukaryotic cells are highly compartmentalized, enabling sophisticated division of labour. For example, genetic information is stored in the nucleus while energy is produced in mitochondria. Despite this clear specialisation, compartments depend on intensive communication, including the exchange of metabolites and macromolecules. This is achieved through intracellular trafficking with membranous carriers such as endosomes, which constitute versatile transport vehicles. Key cargos include mRNAs and ribosomes that hitchhike on endosomes, linking RNA and membrane biology. In this review, we summarize recent advances showing how mRNAs are mechanistically attached to membranes of endosomes and lysosomal vesicles and how cargos are identified for transport. The encoded proteins illuminate the biological processes that rely on such spatiotemporal control. This is particularly true for the regulation of subcellular mitochondrial homeostasis, disclosing intensive multi-organelle networking. As a general concept, the underlying protein/protein and protein/RNA interactions exhibit significant redundancy yet are organized in a strict hierarchy with distinct core and accessory functions. This ensures both the robustness and specificity of mRNA hitchhiking.

Endosymbiosis between dinoflagellate algae and cnidaria is fundamental for coral reef health. Appropriate symbiont selection is required for sufficient host nutrient acquisition and could be tailored to increase cnidarian stress tolerance. Previous research suggested glycan-lectin interactions facilitate symbiont uptake; however, blockage of such interactions does not fully inhibit symbiosis establishment, suggesting other receptors are at play. Here, we use a combination of cnidarian model systems and human cell lines to determine if phagocytic integrins facilitate symbiont recognition and uptake. Integrins are highly expressed in the gastrodermal tissue of the host, where symbiosis takes place, and symbiont uptake alters the expression of integrins and downstream signaling molecules. Blockage of integrin binding sites with competitor peptides reduces symbiont uptake, while uptake of non-symbiotic algae, or uptake in a non-symbiotic cnidarian, is unaffected. Finally, overexpression of phagocytic integrins in human cells increases symbiont uptake, and mutation of the active binding site abolishes uptake. Our findings reveal integrins as important receptors for symbiosis establishment and shed light on the evolutionary functions of integrins during phagocytosis.

During ovariogenesis, more than two-thirds of germ cells are sacrificed to improve the quality of the remaining oocytes. However, the detailed mechanisms behind this selection process are not fully understood in mammals. Here, we developed a high-resolution, four-dimensional ovariogenesis imaging system to track the progression of oocyte fate determination in live mouse ovaries. Through this, we identified a cyst-independent oocyte phagocytosis mechanism that plays a key role in determining oocyte survival. We found that oocytes act as individual cells, rather than connected cyst structures, during ovarian reserve construction. In this process, dominant oocytes capture and absorb cell debris from sacrificed oocytes to enrich their cytoplasm and support their survival. Single-cell sequencing indicated that the sacrificed oocytes are regulated by autophagy. When oocyte sacrifice was inhibited using autophagy inhibitors, the pool of surviving oocytes expanded, but they failed to fully develop and contribute to fertility. Our study suggests that mammals have evolved a cyst-independent selection system to improve oocyte quality, which is essential for sustaining a long reproductive lifespan.

During vertebrate neurogenesis, a transition from symmetric proliferative to asymmetric neurogenic divisions is critical to balance growth and differentiation. Using single-cell RNA-seq data from the chick embryonic neural tube, we identify the cell cycle regulator Cdkn1c as a key regulator of this transition. While Cdkn1 is classically associated with neuronal cell cycle exit, we show that its expression initiates at low levels in neurogenic progenitors. Functionally targeting the onset of this expression impacts the course of neurogenesis: Cdkn1c knockdown impairs neuron production by favoring proliferative symmetric divisions. Conversely, inducing a low-level Cdkn1c misexpression in self-expanding progenitors forces them to prematurely undergo neurogenic divisions. Cdkn1c exerts this effect primarily by inhibiting the CyclinD1-CDK4/6 complex and G1 phase lengthening. We propose that Cdkn1c acts as a dual driver of the neurogenic transition whose low level of expression first controls the progressive entry of progenitors into neurogenic modes of division before higher expression mediates cell cycle exit in daughter cells. This highlights that the precise control of neurogenesis regulators' expression sequentially imparts distinct functions essential for proper neural development.

Melanoma is a highly metastatic form of skin cancer for which current therapies offer limited benefits. We show here that the histone reader ATAD2 is overexpressed in melanoma and predicts poor prognosis, and that the MAP kinase pathway, via the transcription factor E2F1, stimulates ATAD2 expression. Genetic or pharmacological inhibition of ATAD2 suppresses the growth and metastasis of BRAF and NRAS mutant melanoma. Mechanistically, we show that ATAD2 inhibition activates both distinct and common tumor-suppressive pathways in BRAF and NRAS mutant melanoma. In particular, we find that ATAD2 inhibition induces ferroptosis in both contexts by downregulating the ferroptosis suppressor GPX4. The ferroptosis inducer erastin also inhibits melanoma growth. Combining the ATAD2 inhibitor BAY-850 with the MEK inhibitor trametinib potently suppresses melanoma growth. Our study identifies ATAD2 as a key driver of melanoma and provides a rationale for targeting ATAD2 in conjunction with the MAPK pathway to treat melanoma.