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Inflammatory diseases are often chronic and recurrent, and current treatments do not typically remove underlying disease drivers¹. T cells participate in a wide range of inflammatory diseases such as psoriasis², Crohn’s disease³, oesophagitis⁴ and multiple sclerosis^5,6, and clonally expanded antigen-specific T cells may contribute to disease chronicity and recurrence, in part by forming persistent pathogenic memory. Chronic rhinosinusitis and asthma are inflammatory airway diseases that often present as comorbidities⁷. Chronic rhinosinusitis affects more than 10% of the general population⁸. Among these patients, 20–25% would develop nasal polyps, which often require repeated surgical resections owing to a high incidence of recurrence⁹. Whereas abundant T cells infiltrate the nasal polyps tissue^10,11, T cell subsets that drive the disease pathology and promote recurrence are not fully understood. By comparing T cell repertoires in nasal polyp tissues obtained from consecutive surgeries, here we report that persistent CD8⁺ T cell clones carrying effector memory-like features colonize the mucosal tissue during disease recurrence, and these cells characteristically express the tryptase Granzyme K (GZMK). We find that GZMK cleaves many complement components, including C2, C3, C4 and C5, that collectively contribute to the activation of the complement cascade. GZMK-expressing CD8⁺ T cells participate in organized tertiary lymphoid structures, and tissue GZMK levels predict the disease severity and comorbidities better than well-established biomarkers such as eosinophilia and tissue interleukin-5. Using a mouse asthma model, we further show that GZMK-expressing CD8⁺ T cells exacerbate the disease in a manner dependent on the proteolytic activity of GZMK and complements. Genetic ablation or pharmacological inhibition of GZMK after the disease onset markedly alleviates tissue pathology and restores lung function. Our work identifies a pathogenic CD8⁺ memory T cell subset that promotes tissue inflammation and recurrent airway diseases by the effector molecule GZMK and suggests GZMK as a potential therapeutic target.

Argonaute proteins are categorized into AGO and PIWI clades. Across most animal species, AGO-clade proteins are widely expressed in various cell types, and regulate normal gene expression¹. By contrast, PIWI-clade proteins predominantly function during gametogenesis to suppress transposons and ensure fertility^1,2. Both clades use nucleic acid guides for target recognition by means of base pairing, crucial for initiating target silencing, often through direct cleavage. AGO-clade proteins use a narrow channel to secure a tight guide–target interaction³. By contrast, PIWI proteins feature a wider channel that potentially allows mismatches during pairing, broadening target silencing capability^4,5. However, the mechanism of PIWI-mediated target cleavage remains unclear. Here we demonstrate that after target binding, PIWI proteins undergo a conformational change from an ‘open’ state to a ‘locked’ state, facilitating base pairing and enhancing target cleavage efficiency. This transition involves narrowing of the binding channel and repositioning of the PIWI-interacting RNA–target duplex towards the MID-PIWI lobe, establishing extensive contacts for duplex stabilization. During this transition, we also identify an intermediate ‘comma-shaped’ conformation, which might recruit GTSF1, a known auxiliary protein that enhances PIWI cleavage activity⁶. GTSF1 facilitates the transition to the locked state by linking the PIWI domain to the RNA duplex, thereby expediting the conformational change critical for efficient target cleavage. These findings explain the molecular mechanisms underlying PIWI–PIWI-interacting RNA complex function in target RNA cleavage, providing insights into how dynamic conformational changes from PIWI proteins coordinate cofactors to safeguard gametogenesis.

Foraminifera are ubiquitous marine protists that intracellularly accumulate phosphate¹, an important macronutrient in marine ecosystems and in fertilizer potentially leaked into the ocean. Intracellular phosphate concentrations can be 100–1,000 times higher than in the surrounding water¹. Here we show that phosphate storage in foraminifera is widespread, from tidal flats to the deep sea. The total amount of intracellular phosphate stored in the benthic foraminifer Ammonia confertitesta in the Wadden Sea during a bloom is as high as around 5% of the annual consumption of phosphorus (P) fertilizer in Germany. Budget calculations for the Southern North Sea and the Peruvian Oxygen Minimum Zone indicate that benthic foraminifera may buffer riverine P runoff for approximately 37 days at the Southern North Sea and for about 21 days at the Peruvian margin. This indicates that these organisms are probably relevant for marine P cycling—they potentially buffer anthropogenic eutrophication in coastal environments. Phosphate is stored as polyphosphate in cell organelles that are potentially acidocalcisomes. Their metabolic functions can range from regulation of osmotic pressure and intracellular pH to calcium and energy storage. In addition, storage of energetic P compounds, such as creatine phosphate and polyphosphate, is probably an adaptation of foraminifera to O₂ depletion.

Nucleophilic aromatic substitutions (S_NAr) are amongst the most widely used processes in the pharmaceutical and agrochemical industries^1–4, allowing convergent assembly of complex molecules through C–C and C–X (X = O, N, S) bond formation. S_NAr reactions are typically carried out using forcing conditions, involving polar aprotic solvents, stoichiometric bases and elevated temperatures, which do not allow for control over reaction selectivity. Despite the importance of S_NAr chemistry, there are only a handful of selective catalytic methods reported that rely on small organic hydrogen-bonding or phase-transfer catalysts^5–11. Here we establish a biocatalytic approach to stereoselective S_NAr chemistry by uncovering promiscuous S_NAr activity in a designed enzyme featuring an activated arginine¹². This activity was optimized over successive rounds of directed evolution to afford an engineered biocatalyst, S_NAr1.3, that is 160-fold more efficient than the parent and promotes the coupling of electron-deficient arenes with carbon nucleophiles with near-perfect stereocontrol (>99% e.e.). S_NAr1.3 can operate at a rate of 0.15 s^-1, perform >4000 turnovers and can accept a broad range of electrophilic and nucleophilic coupling partners, including those that allow construction of challenging 1,1-diaryl quaternary stereocentres. Biochemical, structural and computational studies provide insights into the catalytic mechanism of S_NAr1.3, including the emergence of a halide binding pocket shaped by key catalytic residues Arg124 and Asp125. This study brings a landmark synthetic reaction into the realm of biocatalysis to provide an efficient and versatile platform for catalytic S_NAr chemistry.

Graphene is a single-layered sp²-hybridized carbon allotrope, which is impermeable to all atomic entities other than hydrogen^1,2. The introduction of defects allows selective gas permeation^3,4,5; efforts have been made to control the size of these defects for higher selectivity^6,7,8,9. Permeation of entities other than gases, such as ions^10,11, is of fundamental scientific interest because of its potential application in desalination, detection and purification^{12,13,14,15,16}. However, a precise experimental observation of halide permeation has so far remained unknown^{11,15,16,17,18}. Here we show halide permeation through a single benzene-sized defect in a molecular nanographene. Using supramolecular principles of self-aggregation, we created a stable bilayer of the nanographene^{19,20,21,22,23}. As the cavity in the bilayer nanographene could be accessed only by two angstrom-sized windows, any halide that gets trapped inside the cavity has to permeate through the single benzene hole. Our experiments reveal the permeability of fluoride, chloride and bromide through a single benzene hole, whereas iodide is impermeable. Evidence for high permeation of chloride across single-layer nanographene and selective halide binding in a bilayer nanographene provides promise for the use of single benzene defects in graphene for artificial halide receptors^24,25, as filtration membranes²⁶ and further to create multilayer artificial chloride channels.

Correction to: Nature https://doi.org/10.1038/nature19326 Published online 24 August 2016