Cell最新文献

Intratumor bacteria represent an understudied yet influential component of the cancer ecosystem, critically impinging cancer progression. In PyMT breast tumors, we find intracellular bacteria, when residing in cancer cell cytosol, promote metastasis by triggering cytosolic double-stranded DNA (dsDNA) accumulation, which in turn activates the tumor intrinsic cGAS-STING-interleukin (IL)-17B pathway and redirects neutrophils toward a protumor phenotype that inhibits cytotoxic T cells. By contrast, the same strain of bacteria, when present extracellularly, induces antitumor neutrophil activity without engaging the STING pathway. Physiologically, eliminating intracellular bacteria, or therapeutically introducing extracellular bacteria components, abrogates immunosuppression and prevents postsurgical metastatic recurrence in preclinical models. Clinically, the bacteria invasion signature we have developed is associated with poor prognosis in patients with breast cancer. In summary, the spatial interplay between bacteria and host cells in metastatic niches can shape divergent tumor immunity, highlighting bacterial-host engagement as a crucial determinant of cancer immune regulation and a potential therapeutic target.

The human gut is a dynamic environment, where changes in pH, oxygen, and osmolality influence microbiota composition and disease. Monitoring these environmental shifts is crucial for advancing gut health diagnostics and therapeutics, yet non-invasive monitoring tools remain limited. Genetically tractable commensals, including Bacteroides thetaiotaomicron, offer promising chassis for engineering biosensors but lack modular systems for precise sensing and reporting. Here, we developed genetic tools for B. thetaiotaomicron, including (1) repressible promoters for tunable fluorescent protein expression, (2) a DNA-based system to modulate repressor activity, (3) a modular, fluorescence-based transcriptional reporter circuit, and (4) an alternative plasmid integration mode. Using these components, we engineered biosensors to detect increased gut osmolality caused by malabsorption and validated them in vitro and in a murine model of laxative-induced osmotic diarrhea. These biosensors enabled long-term, non-invasive reporting of gut osmolality from single-cell fluorescence, demonstrating the potential of gut bacteria as monitoring platforms in gut health applications.

Aggregation of the protein tau defines tauopathies, the most common age-related neurodegenerative diseases, which include Alzheimer's disease and frontotemporal dementia. Specific neuronal subtypes are selectively vulnerable to tau aggregation, dysfunction, and death. However, molecular mechanisms underlying cell-type-selective vulnerability are unknown. To systematically uncover the cellular factors controlling the accumulation of tau aggregates in human neurons, we conducted a genome-wide CRISPRi screen in induced pluripotent stem cell (iPSC)-derived neurons. The screen uncovered both known and unexpected pathways, including UFMylation and GPI anchor biosynthesis, which control tau oligomer levels. We discovered that the E3 ubiquitin ligase CRL5^SOCS4 controls tau levels in human neurons, ubiquitinates tau, and is correlated with resilience to tauopathies in human disease. Disruption of mitochondrial function promotes proteasomal misprocessing of tau, generating disease-relevant tau proteolytic fragments and changing tau aggregation in vitro. These results systematically reveal principles of tau proteostasis in human neurons and suggest potential therapeutic targets for tauopathies.

Although ATP-independent chaperones assist RNA folding, the mechanisms by which they function remain elusive. Here, we demonstrate how two RNA chaperones collaborate to unfold misfolded noncoding RNAs (ncRNAs). The ring-shaped Ro60 protein binds the ends of misfolded ncRNAs in its cavity, whereas La stabilizes nascent ncRNAs and assists their folding. Using cryo-electron microscopy to resolve the structure of a misfolded RNA complexed with Ro60 and La, we show that La cradles the Ro60 ribonucleoprotein (RNP), with its N-terminal domain binding the RNA 3' end after it passes through the Ro60 cavity, while its C-terminal domain destabilizes structures in the misfolded RNA body. Using selective 2'-hydroxyl acylation analyzed by primer extension and mutational profiling (SHAPE-MaP), we show that La and Ro60 function synergistically to unfold non-native structures. As the RNAs bound by Ro60 and La include both ncRNA precursors and ncRNAs with oligouridine tails, this RNA chaperone machine may function widely to recognize misfolded and otherwise aberrant ncRNAs and assist their unfolding.