Cell最新文献

Blood factors transfer the benefits of exercise to the aged brain independent of physical activity. Here, we show that the liver-derived exercise factor (exerkine) glycosylphosphatidylinositol (GPI)-specific phospholipase D1 (GPLD1), a GPI-degrading enzyme, reverses aging- and Alzheimer's-related memory loss by targeting the brain vasculature. GPLD1 has the potential to cleave over 100 putative GPI-anchored proteins, necessitating the identification of downstream targets that mediate cognitive rejuvenation for translational application. We identified GPI-anchored tissue-nonspecific alkaline phosphatase (TNAP) on the brain vasculature as a GPLD1 substrate. Mimicking age-related increases in cerebrovascular TNAP impaired blood-brain transport and cognition in young mice and mitigated GPLD1-induced cognitive benefits in aged mice. Inhibiting TNAP recapitulated the benefits of GPLD1 in old age, restoring youthful hippocampal transcriptional signatures and rescuing cognition. In an Alzheimer's disease model, increasing GPLD1 or inhibiting TNAP ameliorated Aβ pathology and improved cognitive deficits. We thus identify brain vasculature as a mediator of the cognitive benefits of a liver-to-brain exercise axis.

Clearance of aberrant cerebral amyloid-β (Aβ) deposits represents a promising therapeutic strategy for Alzheimer's disease (AD), yet current anti-Aβ immunotherapy raises safety concerns due to frequent adverse effects. Extracellular targeted protein degradation (eTPD) offers an approach for safe and efficient clearance of disease-causing proteins. Here, we develop a next-generation eTPD platform, synthetic peptide-programmed lysosome-targeting chimeras (SPYTACs), using entirely synthesized bispecific peptides. Leveraging low-density lipoprotein receptor-related protein 1 (LRP1), SPYTACs effectively facilitate targeted degradation of extracellular proteins and enable transcytosis across the blood-brain barrier. In vivo administration of SPYTACs effectively reduces peripheral and cerebral Aβ burden, attenuates synapse loss, and improves cognitive function in 5×FAD mice at both prodromal and symptomatic stages. Notably, SPYTAC treatment shows fewer side effects, including intracerebral hemorrhage and inflammation, compared with conventional immunotherapies. The high modularity and genetic encodability enable SPYTACs to target customized disease-causing proteins, underscoring their therapeutic versatility and translational promise across diverse diseases driven by pathogenic proteins.

New World hantaviruses cause severe infections in humans. Previous structural studies have advanced our understanding of hantavirus glycoprotein architecture; however, the lack of high-resolution structures of the glycoprotein tetramer and its lattice organization has limited mechanistic insights into viral assembly and entry. Here, we leveraged a virus-like particle (VLP) system to establish a cryo-electron microscopy workflow for lattice-forming viral glycoproteins. This enabled the determination of a 2.35 Å resolution structure of the membrane-embedded Andes virus (ANDV) glycoprotein tetramer as well as the structures of dimers of tetramers and a complex with antibody ADI-65534. These structures reveal previously uncharacterized features of glycoprotein organization, stability, and pH sensing. The immunization of mice with self-amplifying replicon RNA (repRNA) encoding ANDV-VLPs elicited high levels of glycoprotein-binding antibodies but equivalent titers of neutralizing antibodies compared with the repRNA-encoded native ANDV glycoprotein complex. These findings advance our understanding of hantavirus glycoprotein assemblies, laying a foundation for structure-based vaccine design.

Glycolysis is a central metabolic pathway that converts glucose into pyruvate. Although pyruvate has been well documented to be a key and terminal metabolite of glycolysis with both energetic and biosynthetic roles, its non-metabolic functions remain unexplored. Here, we report a pyruvate-mediated protein post-translational modification (PTM), protein pyruvylation. We reveal that high glucose-upregulated glycolysis promotes signal transducer and activator of transcription 1 (STAT1) pyruvylation at Lys201 (K201), which blocks STAT1 and signal transducer and activator of transcription 2 (STAT2) interaction, thus suppressing type I interferon (IFN-I) signaling and antiviral immune activity. Consequently, STAT1-K201R knockin mice exhibit enhanced IFN-I antiviral immunity. Importantly, high glucose promotes STAT1 pyruvylation and attenuates immune response to either virus infection or IFN-I treatment in humans. This study identifies the protein pyruvylation modification, reveals a non-metabolic function of the metabolite pyruvate, and provides insights into how high glucose impairs IFN-I antiviral immunity through pyruvate, offering strategies to improve IFN-I immune activity for both preventing and treating viral infections.

The tricarboxylic acid (TCA) cycle couples nutrient oxidation with the generation of reducing equivalents that power oxidative phosphorylation. Nevertheless, the requirement for components of the TCA cycle is context-specific, raising the question of which TCA cycle outputs support cell fitness. Here, we demonstrate that citrate clearance is an essential function of the TCA cycle. As citrate production increases, so do TCA cycle activity and dependence upon aconitase 2 (ACO2), the enzyme that initiates citrate catabolism in the TCA cycle. Disrupting citrate catabolism activates the integrated stress response and impairs cell fitness, and these effects are reversed by preventing citrate production or promoting mitochondrial citrate efflux. In vivo, ACO2 deficiency induces citrate accumulation and triggers tubular degeneration in the kidney, a tissue that physiologically takes up circulating citrate. Thus, intracellular citrate accumulation can be a metabolic liability, and citrate clearance is a major function of ACO2 in the TCA cycle.

Nuclear speckles are conserved, membrane-less organelles linked to various post-transcriptional processes. Here, we examined their roles in human cells by engineered, acute removal of SON and SRRM2, two conserved speckle core components characterized by intrinsically disordered regions (IDRs). Their removal results in a significant downregulation of GC-rich genes with short introns clustered within GC-rich isochores, caused by inefficient and chaotic splicing; in contrast, the expression or splicing of genes outside these isochores remains unaffected. Comparative analysis across eukaryotes, from fungi to mammals, reveals that both GC-rich isochores and speckles are found exclusively in amniotes; moreover, the IDRs of SON have undergone notable expansion in the latter. Together, these findings suggest that the expansion of IDRs in vertebrates facilitated an increase in GC content by creating a condensate essential for splicing the by-products of this process: GC-rich, leveled exon-intron architectures.

Vitamins are essential metabolites that must be obtained from external sources. In modern times, they have become widely available, leading to their ad hoc consumption. We developed a nutritional genomics framework to systematically identify monogenic diseases responsive to micronutrient modulation. Genome-wide CRISPR screens under varying vitamin B2 and B3 levels revealed dozens of candidate disease genes amenable to rescue by individual vitamins. In the vitamin B3 screen, NAD(P)HX dehydratase (NAXD) was the top hit; this enzyme repairs an aberrant, hydrated form of NADH (6-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide [NADHX]), and its loss causes severe neurodevelopmental disease. In our Naxd knockout (KO) mouse, we observed NADHX accumulation, NAD⁺ depletion, and impaired serine biosynthesis in neonatal KO brains. Spatial metabolomics, single-nuclei RNA sequencing (snRNA-seq), and histology pinpointed cortical and brain endothelial cell vulnerability. Low-vitamin B3 diets accelerated pathology, whereas vitamin B3 supplementation extended lifespan by more than 40-fold. These findings establish a nutritional genomics framework and demonstrate the therapeutic potential of precision vitamin interventions.