Current Biology最新文献

Energy is a limited resource for living organisms, with trade-offs in expenditure evident among physiological tasks. The impact of physical activity on these trade-offs is currently debated. Additive models, which predominate in human nutrition and animal ecology, suggest physical activity does not affect other expenditure. Recently proposed constrained models propose that increases in physical activity lead to decreases in other expenditure, maintaining total energy expenditure within a narrow range. Here, we develop quantitative frameworks for both models and compare their predictions against data from experimental studies that manipulate physical activity and ecological studies that measure physical activity and expenditure in free-living populations. In human aerobic exercise interventions, total daily energy expenditure increased by only ∼30% of the change expected from additive models. Compensation appeared to be reduced with resistance training and amplified when aerobic exercise is paired with diet restriction. In animal experiments, which often involve some form of dietary restriction, compensation is generally ∼100%. Results from experimental studies are consistent with those of ecological studies, which indicate the degree of compensation to physical activity may be greater in the presence of limited food availability. Reductions in basal metabolic rate and sleeping metabolic rate contribute to energy compensation, particularly in animal studies and longer-duration human studies, but do not fully account for the observed compensation in total daily energy expenditure.

Archaea of the order Sulfolobales possess a eukaryote-like cell division machinery and display a eukaryote-like cell cycle; however, the cell division and cell-cycle control mechanisms remain enigmatic. Here, we demonstrate that phosphorylation of the α subunit by a eukaryote-like protein kinase, ePK2, affects 20S proteasome assembly and controls cell division in Saccharolobus islandicus. ePK2 exhibits cell-cycle-dependent expression at both transcriptional and translational levels. Deletion or overexpression of epk2 results in impaired cytokinesis, with the deletion cells being unable to generate single chromosome cells after synchronization and the overexpression cells exhibiting growth retardation and cell enlargement. Interestingly, overexpression of ePK2 leads to a coherent reduction in cellular proteasome activity and degradation of cell division proteins. We identify S200 and T213 of the proteasome α subunit as specific target sites for ePK2 phosphorylation. Functional analyses of site-directed mutants at S200 and T213 suggest that phosphorylation at these two residues disrupts the assembly of de novo 20S proteasome. Collectively, our study uncovers an ingenious and efficient mechanism of proteasome phosphorylation-mediated cell division regulation, a prototype of the eukaryotic cell-cycle regulation system, in Sulfolobales archaea.

Cell migration is crucial for development and tissue homeostasis, while its dysregulation leads to severe pathologies. Cell migration is driven by the extension of actin-based lamellipodial protrusions powered by actin polymerization, which is tightly regulated by signaling pathways, including Rho GTPases and calcium (Ca²⁺) signaling. While the importance of Ca²⁺ signaling in lamellipodial protrusions has been established, the molecular mechanisms linking Ca²⁺ to lamellipodia assembly are unknown. Here, we identify a novel Ca²⁺ signaling axis involving the mechano-gated channel transient receptor potential vanilloid 4 (TRPV4), which regulates lamellipodial protrusions in various cell types. Using Ca²⁺ and Förster resonance energy transfer (FRET) imaging, we demonstrate that TRPV4-mediated Ca²⁺ influx upregulates RhoA activity within lamellipodia, which then facilitates formin-mediated actin assembly. Mechanistically, we identify Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) and tumor endothelial marker 4 (TEM4) as key mediators relaying the TRPV4-mediated Ca²⁺ signal to RhoA. These data define a molecular pathway by which Ca²⁺ influx regulates small GTPase activity within a specific cellular domain-lamellipodia-and demonstrate its critical role in organizing the actin machinery and promoting cell migration in diverse biological contexts.

Photosymbioses provide carbon and oxygen to the biosphere, yet the mechanisms underlying their evolution remain poorly understood. We develop a naive system based on the predatory ciliate Tetrahymena thermophila, not known for hosting symbionts, to recapitulate early events of photosymbiosis evolution. Tetrahymena thermophila readily phagocytoses eukaryotic algae (Chlorella variabilis) or cyanobacteria (Synechococcuselongatus). Feeding on either prey in a low-carbon medium provided little or no growth advantage. By contrast, in a hypoxic environment, both intracellular C. variabilis and S. elongatus can support temporary survival of T. thermophila. These results suggest that oxygen supply within the host could represent a more plausible initial advantage supporting photosymbiosis evolution than carbon metabolites. While most extant photosymbioses are based on carbon supply to the host cell, we therefore propose that this would be a secondary event occurring from initial evolution in anoxic or hypoxic conditions, where O₂ production is crucial for establishing the initial steps of photosymbiosis.

Learning is vital for animal survival, but it must balance two conflicting demands: sensitivity (to avoid false negatives) and specificity (to avoid false positives). Improving one often worsens the other. Using Drosophila olfactory learning, we unravel how animals successfully perform both tasks. In Drosophila, odors are sparsely represented by cholinergic Kenyon cells (KCs). KCs form lateral axonal connections mediated by the muscarinic type-B receptor (mAChR-B), which suppresses non-specific learning. Using functional imaging, behavior, electrophysiology, and mathematical modeling, we show that mAChR-B is voltage dependent, switching between high- and low-activity states. In its high-activity state, it blocks plasticity in inactive KCs, whereas in its low-activity state, it permits plasticity in active KCs. This voltage-dependent switch enables differential neuromodulation, allowing learning to be both efficient and specific, minimizing both error types. Our findings reveal a novel mechanism for precise neuromodulatory control, reshaping our understanding of neuronal communication.

Flavonoids, produced by the plant under nutrient stress, are required to initiate the legume-rhizobia symbiosis through the activation of rhizobial nod genes. Notwithstanding the central role of flavonoids in nodulation, their transcriptional regulation remains poorly understood. Here, we show that the nodulation signaling pathway 2 (NSP2) is required for transcriptional activation of flavonoid biosynthesis genes during nodulation in Medicago truncatula. Furthermore, MYB40, a legume-specific MYB transcription factor, is induced by rhizobia in the root epidermis. MYB40 directly binds to flavonoid biosynthetic gene promoters and is required for normal levels of nodulation. Biochemical and genetic evidence reveal that NSP2, not NSP1, interacts with MYB40 during rhizobial infection to strongly upregulate the symbiotic gene chalcone O-methyltransferase 1 in a manner dependent on MYB40 binding sites. Moreover, the overexpression of MYB40 and a microRNA-resistant NSP2 variant enhances nodulation under suboptimal rhizobial availability, suggesting this module fine-tunes symbiosis efficiency. Additionally, flavonoid regulation by NSP2 and MYB40 appears to facilitate arbuscular mycorrhizal colonization under nutrient starvation. Together, our findings establish an NSP2-MYB40 module that integrates symbiotic signaling with metabolic reprogramming, representing an evolutionary innovation for optimizing nitrogen acquisition in dynamic environments.

Circadian clocks are phylogenetically widespread timekeeping mechanisms that provide a fitness-enhancing ability to anticipate time-of-day changes in the environment.^1,2,3 A ubiquitous and defining feature of all circadian clocks is their ability to maintain self-sustained oscillations in constant conditions (i.e., constant temperature and constant light or constant darkness), despite the fact that they evolved on Earth, where constant environments are almost unknown.^4,5 Damped circadian oscillators can entrain competently to daily light/dark cycles, and even "hourglass" timers can provide temporal order in many environments.⁶ So, why has the self-sustained property of daily timekeepers been so universally selected to the extent that it is a defining property of circadian systems? An extensive modeling analysis of this question concluded that the daily and seasonal variability of environmental fluctuations in both weather (e.g., temperature, light intensity) and seasonal daylength together demanded self-sustained clocks.⁷ However, our experimental analysis of this investigation, based on competition among strains expressing differing phenotypes,^2,3,5 revealed that changing photoperiods, such as those encountered over the annual cycle of seasons, are a sufficient environmental pressure to select for self-sustained circadian oscillators, even in the absence of fluctuations in other environmental factors. The salient properties of daily circadian clocks are therefore molded by modulations of environmental cycles of multiple periodicities, both daily and annual/seasonal.

Mitochondria contain a genome (mtDNA) encoding a handful of proteins essential for cellular respiration. mtDNA can leak into the cytosol and drive fitness defects. The first genes associated with mtDNA escape were discovered in yeast and aptly named "yeast mitochondrial escape" (YME) genes. We identify the mechanism by which an intermembrane space nuclease, endonuclease G (human ENDOG; yeast Nuc1), prevents mtDNA escape to the cytosol in yeast. Nuc1 nuclease activity and mitochondrial localization are essential for preventing mtDNA escape and suggest a direct role of Nuc1 in degrading mtDNA bound for escape. We find that blocking autophagy via atg1 and atg8 mutants prevents mtDNA escape in the absence of Nuc1. We further demonstrate that blocking mitophagy via atg11 and atg32 mutants prevents mtDNA escape, whereas inducing mitophagy increases mtDNA escape in the absence of Nuc1. Finally, we demonstrate that Nuc1 degrades mtDNA bound for escape via the vacuole, as an atg15 mutant that prevents disassembly of autophagic bodies in the vacuole also prevents mtDNA escape. Overall, our results implicate vacuolar entry of mitochondria during mitophagy as an important mtDNA escape pathway in yeast, which is normally mitigated via the degradation of mtDNA by Nuc1.

Understanding the mechanisms underlying homeostatic sleep regulation is a central, unmet goal of sleep science. Our comprehension of such regulation in mammals has required recognizing distinct sleep stages. Drosophila melanogaster is an important genetic model system for studying sleep. Since the discovery of sleep-like states in the fly 25 years ago, the field has treated sleep as a unitary state consisting of any inactivity lasting 5 min or longer, despite convergent work suggesting the existence of multiple sleep states. Here, we establish that three distinct sleep states in flies can be classified based on simple inactivity duration criteria. We show that the daily initiation of these sleep states is temporally distinct, with long sleep occurring immediately following the largest daily period of wakefulness. We also report that the rebound in response to mechanical sleep deprivation is present only in long sleep and comes at the expense of shorter sleep states. Deprivation-induced decreases in shorter sleep states obscure homeostatic sleep rebound, but only when sleep is measured using traditional methods. We observe distinctly timed ultradian oscillations of fly sleep states, reminiscent of mammalian sleep cycles. Our results indicate that the recognition of such sleep states will be necessary to fully realize the promise of the Drosophila model system for identifying conserved genetic mechanisms underlying sleep regulation.