Cell reports最新文献

tRNA modifications are critical for several aspects of their functions, including decoding, folding, and stability. Using a multifaceted approach encompassing eCLIP-seq and nanopore tRNA-seq, we show that the human tRNA methyltransferase TRMT1L interacts with the component of the Rix1 ribosome biogenesis complex and binds to the 28S rRNA as well as to a subset of tRNAs. Mechanistically, we demonstrate that TRMT1L is responsible for catalyzing N2,N2-dimethylguanosine (m²₂G) solely at position 27 of tRNA-Tyr-GUA. Surprisingly, TRMT1L depletion also impaired the deposition of 3-(3-amino-3-carboxypropyl) uridine (acp³U) and dihydrouridine on tRNA-Tyr-GUA, Cys-GCA, and Ala-CGC. TRMT1L knockout cells have a marked decrease in tRNA-Tyr-GUA levels, coinciding with a reduction in global translation rates and hypersensitivity to oxidative stress. Our results establish TRMT1L as the elusive methyltransferase catalyzing the m²₂G27 modification on tRNA Tyr, resolving a long-standing gap of knowledge and highlighting its potential role in a tRNA modification circuit crucial for translation regulation and stress response.

Caenorhabditis elegans proliferates poorly in the presence of abundant Actinobacteria from its natural ecology, but it is unknown why. Here, we show how perturbed levels of hydrogen sulfide modulate the growth rate of both C. elegans and Actinobacteria. From a forward genetic selection, we find C. elegans mutants with faster growth on an Actinobacteria Microbacterium species and mutant alleles of conserved cystathionine gamma-lyase (cth-2/CTH) that improve growth rate. Conversely, null alleles of cth-2 cause developmental arrest of animals grown on Actinobacteria, but not on Proteobacteria, which can be rescued by exogenous H₂S. We also find mutations in a leucine-rich-repeat gene that regulates cysteine and H₂S production, lrr-2/LRRC58. We place lrr-2 in the animal sulfur metabolism pathway by demonstrating its role in post-translationally regulating levels of cysteine dioxygenase (cdo-1/CDO1). Exogenously supplied H₂S inhibits the growth of Actinobacteria but not Proteobacteria. Thus, we conclude that the C. elegans-Actinobacteria interaction is mediated by H₂S.

Words represent a uniquely human information channel-humans use words to express thoughts and feelings and to assign emotional valence to experience. Work from model organisms suggests that valence assignments are carried out in part by the neuromodulators dopamine, serotonin, and norepinephrine. Here, we ask whether valence signaling by these neuromodulators extends to word semantics in humans by measuring sub-second neuromodulator dynamics in the thalamus (N = 13) and anterior cingulate cortex (N = 6) of individuals evaluating positive, negative, and neutrally valenced words. Our combined results suggest that valenced words modulate neuromodulator release in both the thalamus and cortex, but with region- and valence-specific response patterns, as well as hemispheric dependence for dopamine release in the anterior cingulate. Overall, these experiments provide evidence that neuromodulator-dependent valence signaling extends to word semantics in humans, but not in a simple one-valence-per-transmitter fashion.

Loss of dopaminergic neurons in Parkinson's disease (PD) is preceded by loss of synaptic dopamine (DA) and accumulation of proteinaceous aggregates. Linking these deficits is critical to restoring DA signaling in PD. Using murine and human pluripotent stem cell (hPSC) models of PD coupled with human postmortem tissue, we show that accumulation of α-syn micro-aggregates impairs metabolic flux through the pentose phosphate pathway (PPP). This leads to decreased nicotinamide adenine dinucleotide phosphate (NADP/H) and glutathione (GSH) levels, resulting in DA oxidation and decreased total DA levels. We find that α-syn anchors the PPP enzyme G6PD to synaptic vesicles via the α-syn C terminus and that this interaction is lost in PD. Furthermore, G6PD clinical mutations are associated with PD diagnosis, and G6PD deletion phenocopies PD pathology. Finally, we show that restoring NADPH or GSH levels through genetic and pharmacological intervention blocks DA oxidation and rescues steady-state DA levels, identifying G6PD as a pharmacological target against PD.

Neuronal populations expand their information-encoding capacity using mixed selective neurons. This is particularly prominent in association areas such as the lateral prefrontal cortex (LPFC), which integrate information from multiple sensory systems. However, during conditions that approximate natural behaviors, it is unclear how LPFC neuronal ensembles process space- and time-varying information about task features. Here, we show that, during a virtual reality task with naturalistic elements that requires associative memory, individual neurons and neuronal ensembles in the primate LPFC dynamically mix unconstrained features of the task, such as eye movements, with task-related visual features. Neurons in dorsal regions show more selectivity for space and eye movements, while ventral regions show more selectivity for visual features, representing them in a separate subspace. In summary, LPFC neurons exhibit dynamic and mixed selectivity for unconstrained and constrained task elements, and neural ensembles can separate task features in different subspaces.

Organisms allocate energetic resources between essential cellular processes to maintain homeostasis and, in turn, maximize fitness. The nutritional regulators of energy homeostasis have been studied in detail; however, how developmental signals might impinge on these pathways to govern metabolism is poorly understood. Here, we identify a non-canonical role for Hedgehog (Hh), a classic regulator of development, in maintaining intestinal lipid homeostasis in Caenorhabditis elegans. We demonstrate, using C. elegans and mouse hepatocytes, that Hh metabolic regulation does not occur through the canonical Hh transcription factor TRA-1/GLI, but rather via non-canonical signaling that engages mammalian target of rapamycin complex 2 (mTORC2). Hh mutants display impaired lipid homeostasis, decreased growth, and upregulation of autophagy factors, mimicking loss of mTORC2. Additionally, we find that Hh inhibits p38 MAPK signaling in parallel to mTORC2 activation to modulate lipid homeostasis. Our findings reveal a non-canonical role for Hh signaling in lipid metabolism via regulation of core homeostatic pathways.

Granulocytes exert several effector mechanisms, including the release of DNA traps during ETosis. While bacteria-induced ETosis has been linked to the non-canonical inflammasome pathway, the role of the inflammasome activation during ETosis in response to extracellular pathogens has not been investigated. The current study demonstrates that microfilariae (MF) of the rodent filarial nematode Litomosoides sigmodontis induce eosinophil ETosis via the canonical inflammasome pathway. The absence of key components of the canonical inflammasome, including gasdermin D, caspase-1, the adaptor molecule ASC, or AIM2 (double-stranded DNA sensor) prevents MF-induced DNA release in murine eosinophils. While AIM2 activation is not affecting other effector mechanisms such as reactive oxygen species generation and nuclear membrane collapse, it appears to be critical in mediating the release of DNA from the cell during the later stages of ETosis. Finally, the findings on inflammasome-dependent ETosis in response to MF are confirmed in human eosinophils.

Men, despite having a lower likelihood of longevity compared to women, generally exhibit better health status when they achieve longevity. The role of DNA methylation in this paradox remains unclear. We performed whole-genome bisulfite sequencing on long-lived men (LLMs), long-lived women (LLWs), younger men (YMs) and younger women (YWs) to explore specific methylation characteristics in LLMs. Despite an accelerated methylation aging rate in LLMs compared to LLWs, we identify thousands of differentially methylated genomic units (DMUs) in LLMs independent of age and sex. These DMUs, validated by an elastic net classifier, can serve as methylation markers for discriminating longevity potential in men. Many are located near health-related genes. Genes like PIWIL1 and EXT1, with promoters featuring DMUs, exemplify the potential role of LLM-specific methylation patterns in suppressing age-related diseases by regulating gene transcription. Our findings provide evidence of a distinct methylation feature contributing to healthy aging and longevity of LLMs.

The integrated analysis of histone modifier enzymes in solid tumors, especially in esophageal squamous cell carcinoma (ESCC), is still inadequate. Here, we investigate the expression levels of histone modifier enzymes in ESCC tissues. Notably, KAT8 (lysine acetyltransferase 8) is identified as a prognostic and therapeutic biomarker in ESCC. Esophageal-tissue-specific deletion of KAT8 in mice led to less tumor burden after induction of tumorigenesis via 4-nitroquinoline N-oxide (4NQO) treatment compared with wild-type mice. Meanwhile, silencing KAT8 significantly suppresses tumor growth in cell-line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Mechanically, we confirm that KAT8 regulates c-Myc protein stability by directly binding it. Furthermore, we design and screen a specific KAT8 inhibitor (CHI-KAT8i5) that significantly attenuates tumor growth in vitro and in vivo, providing promising potential for clinical application. Thus, our work identifies that KAT8 could serve as a potential clinically relevant biomarker and therapeutic target in patients with ESCC and that KAT8 inhibitor is a promising lead candidate for ESCC therapy.