Qin J, Cai C, Shan M
… +19 more, Zhou S, Shen Q, Zhu T, Zhao M, Mei Y, Ji F, Shen DD, Zang SK, Zhang H, Xu H, Yang M, Wang WW, Xiao R, Yang B, Mao C, Shao Z, Wu H, Lu Q, Zhang Y
C5a, the most potent anaphylatoxin in the complement system, exerts its effects through the canonical G protein-coupled receptor C5aR1 and the arrestin-coupled receptor C5aR2. Despite the critical role of C5aR2 in immuno...C5a, the most potent anaphylatoxin in the complement system, exerts its effects through the canonical G protein-coupled receptor C5aR1 and the arrestin-coupled receptor C5aR2. Despite the critical role of C5aR2 in immunomodulation, the molecular mechanisms underlying its biased signaling, ligand recognition, and associated pathophysiology remain poorly understood. Here, we report cryo-electron microscopy structures of β-arrestin 1-bound C5aR2 and C5aR1 stimulated by C5a or its metabolite C5a. By combining structural analysis with functional assays, we identified the key structural determinants that prevent G protein coupling and confer intrinsic bias toward β-arrestins. Comparative analysis elucidated the distinct ligand recognition mechanism of C5aR2 and explained the retained affinity of C5a for C5aR2. These findings guided the rational design of ZQ105, a highly selective C5aR2 agonist. Leveraging ZQ105 as a chemical probe, functional studies revealed that selective C5aR2 activation induces distinct pro-inflammatory responses and receptor internalization in neutrophils. This study provides novel structural insights into transducer engagement and ligand recognition by C5aR2, yielding a valuable pharmacological tool for exploring C5aR2-related pathophysiological processes.
Sex pheromones play a central role in regulating animal behavior and reproduction. In insects, these signals are perceived through specialized odorant receptors (ORs) that mediate species-specific communication and safeg...Sex pheromones play a central role in regulating animal behavior and reproduction. In insects, these signals are perceived through specialized odorant receptors (ORs) that mediate species-specific communication and safeguard genetic integrity. However, the structural basis of sex pheromone detection remains largely unresolved. Here, we identified two ORs in the pea aphid Acyrthosiphon pisum, along with the conserved OR co-receptor (Orco), which together mediate recognition of the pheromone components nepetalactone and nepetalactol. Functional assays demonstrated that ApOR21-Orco and ApOR22-Orco specifically respond to nepetalactol and nepetalactone, respectively. Using cryo-electron microscopy, we resolved the structure of the ApOR22-Orco complex in three states - unbound closed, nepetalactone-bound closed, and nepetalactone-bound open - revealing a heterotetrameric ion channel formed by one ApOR22 and three ApOrco subunits. Ligand binding to ApOR22 triggers conformational rearrangements that induce asymmetric pore dilation, thereby enabling ion conduction. Together, these results provide a mechanistic framework for understanding sex pheromone perception in insects and establish a structural foundation for the rational development of environmentally sustainable pest-control strategies.
Pheromones mediate intraspecific communication to regulate the physiology and behavior of animals, particularly insects. The detection of pheromones is initiated by the binding of pheromone molecules, e.g., 11-cis-vaccen...Pheromones mediate intraspecific communication to regulate the physiology and behavior of animals, particularly insects. The detection of pheromones is initiated by the binding of pheromone molecules, e.g., 11-cis-vaccenyl acetate (cVA) in Drosophila, to specific receptor proteins in chemosensory neurons, but the underlying molecular mechanisms remain unclear. Here, we report structures of Drosophila pheromone receptor OR67d-Orco complexes in apo closed, pheromone-bound open, and synthetic agonist VUAA1-bound open conformations. OR67d and Orco assemble into a hetero-tetrameric channel with a 1:3 stoichiometry. In OR67d, the inverted L-shaped cVA or its analog binds into a deep and bent hydrophobic pocket, inducing both local and global conformational changes that lead to an asymmetrical opening of the channel gate. By comparison, VUAA1 binds to Orco instead of OR67d to cause a similar asymmetrical opening. Together, our studies reveal the structural basis for pheromone activation of hetero-tetrameric pheromone receptors.
Emotion induces changes in regional cerebral blood flow, a manifestation of neurovascular coupling (NVC). However, whether NVC provides feedback to actively modulate emotion remains unexplored. Here, we demonstrate that...Emotion induces changes in regional cerebral blood flow, a manifestation of neurovascular coupling (NVC). However, whether NVC provides feedback to actively modulate emotion remains unexplored. Here, we demonstrate that NVC actively and bidirectionally modulates stress-induced negative emotions. We established bidirectional manipulations of NVC in freely moving mice by employing integrated pharmacological, genetic, and arteriolar optogenetic approaches. Our results showed that both systemic and region-specific NVC deficiencies in the basolateral amygdala (BLA) heightened emotional responses when mice transitioned from a safe, familiar environment to anxiogenic environments and that local restoration of NVC in the BLA normalized these responses. Mechanistically, NVC dysfunction impaired the capacity of BLA neuronal scaling during state transitions, manifesting as a characteristic biphasic pattern of c-Fos topology. NVC-deficient animals aberrantly adopted high-stress configurations under mild stress but regressed to low-stress templates during high-demand survival threats, thereby compromising defensive sustainability. Notably, the genetic NVC-enhancement model counteracted NVC impairments caused by chronic stress, thereby alleviating stress-driven emotional distress. These findings establish NVC in the BLA as an allostatic program that fine-tunes neural circuit activity during emotional responses, with implications for understanding and treating emotional disorders.
Metastasis, responsible for > 90% of cancer-related mortality, represents the most lethal yet least mechanistically understood phase of cancer progression. A critical bottleneck is tumor cell migration through physically...Metastasis, responsible for > 90% of cancer-related mortality, represents the most lethal yet least mechanistically understood phase of cancer progression. A critical bottleneck is tumor cell migration through physically confined environments, including dense extracellular matrix, narrow capillaries and endothelial gaps. Although tumor cells reprogram their metabolism to facilitate cancer progression, it remains unclear how specific metabolic adaptations enable them to overcome the unique physical challenges posed by these confined spaces, thereby promoting distant metastasis. We conducted a CRISPR screen targeting 1685 metabolic enzymes and identified dihydrolipoamide dehydrogenase (DLD), a mitochondrial enzyme involved in energy metabolism, as essential for confined migration of tumor cells. Depletion or pharmacological inhibition of DLD suppressed CRC metastasis by impairing tumor cell migration through capillaries and endothelial gaps. Upon mechanical compression, heterogeneous nuclear ribonucleoprotein A0 (hnRNPA0) binds to the adenylate uridylate-rich element (ARE) in the 3'UTR of DLD, enhancing its mRNA stability and upregulating DLD expression in tumor cells during confined migration. Elevated DLD expression enhances tricarboxylic acid (TCA) cycle metabolism, increasing malate levels. Malate interacts with tubulin alpha-1B chain (TUBA1B) to promote microtubule assembly, facilitating confined migration and metastasis. Knock-in of an ARE-deleted DLD mutant (DLD ΔARE) or disruption of the malate-TUBA1B interaction significantly suppressed tumor metastasis. In CRC patients, DLD expression was upregulated in tumor cells within capillaries of primary tumors and correlated with metastatic recurrence. Our findings reveal that compressive forces drive metastatic dissemination by epigenetically reprogramming mitochondrial metabolism, which in turn fuels cytoskeletal remodeling.
Li Z, Zhang Y, Li S
… +25 more, Qu C, Luo D, Ni P, Zong Y, Li X, Sun T, Ye R, Sun R, Zhu Y, Guo T, Tao Z, Chen L, Su K, Zhang Y, Li W, Zhao X, Dong J, Zhang J, Tan Y, Zhang X, Dong F, Xiong L, Huang X, Sheen J, Du H
Industrial activities have driven stratospheric ozone depletion, increasing surface UV-B radiation while exacerbating global warming. These changes limit crop productivity, alter species distributions, and disrupt plant...Industrial activities have driven stratospheric ozone depletion, increasing surface UV-B radiation while exacerbating global warming. These changes limit crop productivity, alter species distributions, and disrupt plant metabolic processes, but the mechanisms linking energy signaling to heat-stress responses remain unclear. Here, we identify the photoreceptor UV RESISTANCE LOCUS 8b (OsUVR8b) as a substrate of SNF1-related protein kinase 1 (SnRK1) in rice and reveal a natural variation at its SnRK1-mediated phosphorylation site (Ser177) that is correlated with adaptation to tropical climates. The thermotolerant OsUVR8b accessions show geographic enrichment in low-latitude regions with elevated temperatures. Functional validation through prime editing demonstrated that a Ser177-to-Ala177 substitution enhances heat tolerance, whereas the reverse edit compromises it. Mechanistically, OsUVR8b exhibits reduced stability and an impaired capacity for scavenging reactive oxygen species under heat stress. The regulatory function of the OsUVR8b Ser177 phosphorylation site, a molecular switch that governs UVR8 stability and thermotolerance, can be functionally re-established across rice, Arabidopsis, tobacco, and soybean, indicating its preservation during domestication. Notably, OsUVR8b maintains higher fertility and yield under non-stress conditions, indicating a tradeoff between heat adaptation and productivity. Our findings thus establish this switch as a key regulator of the yield-resilience balance and a promising target for breeding of climate-resilient crops.