Acute SARS-CoV-2 infection triggers the de novo production of diverse, functional autoantibodies (AABs) that remain elevated in long COVID (LC), but their pathogenic role remains unclear. Using tissue-based immunofluores...Acute SARS-CoV-2 infection triggers the de novo production of diverse, functional autoantibodies (AABs) that remain elevated in long COVID (LC), but their pathogenic role remains unclear. Using tissue-based immunofluorescence, ELISA, human protein array, and mass spectrometry assays, we identified a broad range of AAB targets among individuals with LC. Individuals with neurocognitive symptoms showed increased AABs against central nervous system (CNS) and peripheral nervous system proteins. Purified immunoglobulin G (IgG) reacted with human locus coeruleus, thalamus, adrenal gland, and thyroid and cross-reacted with mouse sciatic nerve and meninges. CNS-reactive AABs correlated with several neurological symptoms. MED20-targeting IgG from patients with LC showed enhanced antibody-dependent phagocytosis. Passive transfer of IgG from individuals with LC into mice induced fatigue-like behavior, loss of balance/coordination, thermal hyperalgesia, small fiber nerve damage, and increased pain-related neuronal activity, recapitulating patients' symptoms. These findings suggest that targeting AABs might offer therapeutic benefits for this LC subgroup.
Aging is characterized by the loss of tissue homeostasis, traditionally captured by the hallmarks of aging, yet how these hallmarks integrate to drive organismal decline remains unresolved. We propose mesenchymal drift,...Aging is characterized by the loss of tissue homeostasis, traditionally captured by the hallmarks of aging, yet how these hallmarks integrate to drive organismal decline remains unresolved. We propose mesenchymal drift, a process in which cells progressively lose lineage identity and adopt mesenchymal features, as a convergent framework that integrates the hallmarks of aging. Accumulating evidence suggests that mesenchymal drift can both arise from and reinforce these hallmarks, forming a feedback network that drives systemic decline. Framing aging through mesenchymal drift shifts the focus from discrete molecular defects to interconnected disruptions in cellular identity and cell state regulation, providing a more cohesive view of aging biology. Mesenchymal drift may therefore represent a measurable and targetable mechanism underlying diverse age-related pathologies. Interventions such as partial reprogramming may restrain mesenchymal drift, restore cellular identity, and simultaneously counteract multiple hallmarks, positioning it as both a convergent nexus and a tractable therapeutic axis in aging biology.
In this issue of Cell, Mao et al. reveal that B cells play an unexpected, immune-independent role in exercise physiology by facilitating multi-organ communication. Secreting TGF-β1, they transcriptionally reprogram hepat...In this issue of Cell, Mao et al. reveal that B cells play an unexpected, immune-independent role in exercise physiology by facilitating multi-organ communication. Secreting TGF-β1, they transcriptionally reprogram hepatic glutamine metabolism via GLS2 and SLC7A5, preserving skeletal muscle glutamate levels, which sustain mitochondrial function, Ca⁺ signaling, and ATP production, enhancing exercise capacity.
Long COVID is a heterogeneous, multi-system disease that poses challenges for patients, health systems, and economies. Two papers in Cell and Cell Reports Medicine from independent groups suggest that autoantibodies in a...Long COVID is a heterogeneous, multi-system disease that poses challenges for patients, health systems, and economies. Two papers in Cell and Cell Reports Medicine from independent groups suggest that autoantibodies in a subset of long COVID patients can directly drive symptoms such as pain, fatigue, or neurocognitive problems.
Two studies in this issue of Cell, by Bintu et al. and Brann et al., overturn the long-standing zonal model of olfactory receptor organization. Using image-based spatial transcriptomics, they reveal that receptors occupy...Two studies in this issue of Cell, by Bintu et al. and Brann et al., overturn the long-standing zonal model of olfactory receptor organization. Using image-based spatial transcriptomics, they reveal that receptors occupy reproducible positions along continuous gradients, coupling receptor choice to axonal targeting through a shared molecular code.
Wang X, Zhang Y, Lu M
… +18 more, Gong Y, Guan T, Hou G, Wei Y, Wang M, Liu H, Huang L, Zheng S, Lin Q, Zhang W, Xiang Z, Ma J, Li L, Meng H, Tong X, Ji H, Huang J, Hu Y
Kirsten Rat Sarcoma viral oncogene homolog (KRAS) is one of the most frequently activated driver genes across human cancers. We identified a regulatory mechanism where KRAS forms condensates in the cytoplasm through liqu...Kirsten Rat Sarcoma viral oncogene homolog (KRAS) is one of the most frequently activated driver genes across human cancers. We identified a regulatory mechanism where KRAS forms condensates in the cytoplasm through liquid-liquid phase separation (LLPS), driven by farnesylation at the C185 residue within its hypervariable region (HVR). These condensates are associated with advanced stages and poor outcomes in colon cancer. Functionally, KRAS condensates efficiently interact with Ras-converting enzyme 1 (RCE1), promoting RCE1 clustering, enhancing KRAS processing, and facilitating its translocation to the plasma membrane, which amplifies KRAS signaling and promotes tumor growth. Growth factor stimulation further elevates KRAS condensate formation, emphasizing its role in tumor biology. Therapeutically, screening US Food and Drug Administration (FDA)-approved drugs revealed that statins, particularly pitavastatin, disrupt KRAS LLPS by inhibiting farnesylation, effectively suppressing colon cancer growth and enhancing the efficacy of G12Ci treatment. These findings uncover LLPS as a mechanism regulating KRAS activity and provide a promising target for therapeutic intervention.
Recognition of Wnt proteins by Frizzled (Fzd) receptors and the low-density lipoprotein receptor-related protein 5/6 (LRP5/6) co-receptor is essential for canonical Wnt signaling. It remains enigmatic how Wnt simultaneou...Recognition of Wnt proteins by Frizzled (Fzd) receptors and the low-density lipoprotein receptor-related protein 5/6 (LRP5/6) co-receptor is essential for canonical Wnt signaling. It remains enigmatic how Wnt simultaneously interacts with Fzd and LRP5/6 and activates intracellular Wnt/β-catenin signaling. Here, we report cryo-electron microscopy (cryo-EM) structures of Wnt3a/Fzd8/LRP6 extracellular complexes captured in a 2:4:2 stoichiometry, consisting of a Wnt3a-Wnt3a homodimer, whereby each Wnt3a monomer binds to two Fzd8 receptors and one LRP6 co-receptor. This implies that Wnt3a induces Fzd cystine-rich domain (Fzd-CRD) tetramerization, which in turn could promote recruitment of oligomeric Disheveled (Dvl) to Fzd on the cytoplasmic side. Indeed, mutations of key Wnt3a-Wnt3a interface residues abolish Fzd-LRP clustering and downstream signaling, supporting a critical role of Wnt3a-Wnt3a dimerization in Wnt signalosome assembly and signaling. Our structures also show how the Wnt3a N-helical domain recognizes the LRP6 extracellular domain (LRP6-ECD) E3 β-propeller, while the Wnt3a N-C hairpin interacts with the valley between LRP6-E3 and -E4 propellers, underpinning the development of targeted Wnt therapeutics.
Zhang H, Zhang Z, Wang P
… +18 more, Xu T, Chen X, Zhao Y, Lin S, Cai W, Ren P, Luo C, Zhang P, Wang Y, Hou S, Zhao Y, Zeng H, Liu Z, Wang C, Gao Z, Feng Y, Pan D, Zeng Z
Spatial omics has advanced our understanding of tissue-level biology, yet tools to systematically link gene functional perturbations to spatial phenotypes and signaling pathways remain limited. To address this, we develo...Spatial omics has advanced our understanding of tissue-level biology, yet tools to systematically link gene functional perturbations to spatial phenotypes and signaling pathways remain limited. To address this, we developed spatial CRISPR screen sequencing (SPAC-seq), a high-throughput spatial CRISPR screen platform, and TARDIS (target prioritization toolkit for perturbation data in spatial omics), a statistical spatial perturbation analysis toolkit. Using SPAC-seq and TARDIS, we linked gene perturbations to spatial phenotypes and pathways, uncovering how Icam1 loss in tumor cells promotes metastasis via immune suppression and macrophage polarization. In CD8 T cells, we revealed Cd44's role in regulating spatial phenotypes by interacting with Spp1 on macrophages. We also demonstrated the model of the transcription factor-chemokine receptor axis coupling cell states with chemotaxis. SPAC-seq and TARDIS provide an effective framework to study spatially resolved functional genomics and pathways across diverse biological and disease contexts.
Detection of α-synuclein (α-syn) amyloid seeds in human biofluids has attracted great interest for clinical diagnosis of synucleinopathies. However, as a common biomarker, α-syn lacks specificity in reliably differentiat...Detection of α-synuclein (α-syn) amyloid seeds in human biofluids has attracted great interest for clinical diagnosis of synucleinopathies. However, as a common biomarker, α-syn lacks specificity in reliably differentiating distinct disorders. Here, we report tubulin polymerization promoting protein (TPPP/p25) as a cerebrospinal fluid (CSF) biomarker for the specific diagnosis of multiple system atrophy (MSA). We demonstrate that native TPPP/p25 is self-protected against amyloid aggregation, while disease-related mutation disrupts this protection, triggering TPPP/p25 aggregation. Cryo-electron microscopy (cryo-EM) analysis reveals that the well-folded core domain (CORE) undergoes large conformational changes to mediate amyloid formation. Based on this insight, we developed a seed amplification assay using a minimized CORE (miniCORE) monomer, which detects TPPP/p25 amyloid seeds in CSF and robustly differentiates MSA from Parkinson's disease (PD) and other neurodegenerative diseases. Our findings establish misfolded TPPP/p25 as a promising, specific biomarker in biofluids for MSA diagnosis.
Tibbs-Cortes LE, Han L, Jewell JB
… +24 more, Singh P, Huang H, Benke R, Trieu T, Tang Z, Choi S, Zhao J, Berenguer EI, Pendergast TH, Liu B, Le T, Swaminathan K, Weng X, Andorf C, Graham MA, Sanguinet K, Zhang Z, Bartley LE, Bao Y, Parrott W, Devos KM, Juenger T, Yu J, Li X
Species occupying broad geographic regions have evolved multiple mechanisms to regulate phenological characteristics, enabling adaptations to diverse native habitats. By developing computer vision AI to process citizen s...Species occupying broad geographic regions have evolved multiple mechanisms to regulate phenological characteristics, enabling adaptations to diverse native habitats. By developing computer vision AI to process citizen science observations across native habitats over North America, we uncovered a consistent latitudinal trend of earlier flowering at higher latitudes in warm-season perennial grasses. To explore the underlying mechanisms of adaptation, we conducted common garden experiments with one species (switchgrass) and discovered the opposite latitudinal flowering-time trend. Integration of differential plasticity of GI-Hd1-FTL1 haplotypes of flowering time regulatory genes, haplotype range, and local environmental profiles found that observations from native habitats capture only part of the genotype-environment-phenotype spectrum established in common garden experiments, therefore reconciling the discrepancy. Two mechanisms emerged as key forces shaping current haplotype ranges and influencing future shifts. Our study highlights the power of combining citizen science observations with designed experiments to uncover mechanisms of adaptation across spatiotemporal scales.
Hepatitis B virus (HBV) infects hepatocytes by specific binding to the cell-surface receptor-sodium taurocholate cotransporting polypeptide (NTCP)-through the preS1 region of its large envelope protein, followed by a les...Hepatitis B virus (HBV) infects hepatocytes by specific binding to the cell-surface receptor-sodium taurocholate cotransporting polypeptide (NTCP)-through the preS1 region of its large envelope protein, followed by a less well-understood transport process across the cytoplasm to the nucleus. Here, we report that scavenger receptor class F member 2 (SCARF2), a single-pass transmembrane protein, functions as an intracellular receptor for HBV. SCARF2 binds to a preS1 region downstream of the NTCP binding site through its N-terminal epidermal growth factor (EGF)-like domains 4-6, and its proline-rich C-terminal domain also plays an indispensable role in the infection. The internalized HBV virions are transported to the cytoplasmic side of nuclear pore complexes within the SCARF2-containing endosomes. HBV nucleocapsid release from the endosomal vesicles is impaired by knockdown of SCARF2. These results suggest a model in which SCARF2 conveys HBV to the periphery of nuclear pore complexes (NPCs) and ultimately leads to viral nucleocapsid release for nuclear entry.
Maurais EG, Mazzagatti A, Lin YF
… +13 more, Narozna M, Hu Q, Dahiya R, Santiago-Ferrer D, Herlihy CP, Krebs M, Pateraki N, Parcharidou E, Papathanasiou S, Beliveau BJ, Gorbsky GJ, Cortés-Ciriano I, Ly P
The mammalian genome is safeguarded within the confines of the interphase nucleus. However, genomic instability can trigger the mislocalization of nuclear DNA to the cytoplasm within micronuclei or as fragmented chromoso...The mammalian genome is safeguarded within the confines of the interphase nucleus. However, genomic instability can trigger the mislocalization of nuclear DNA to the cytoplasm within micronuclei or as fragmented chromosomes. Beyond activating cell-autonomous signaling programs, whether such cytoplasmic DNA can elicit non-cell-autonomous consequences to nearby cells remains unclear. Here, we show that cytoplasmic DNAs undergo intercellular transfer through contact-dependent, cytoskeleton-based nanotube structures connecting adjacent human cells. Diverse sources of genomic instability-including exposure to mitotic spindle poisons, ionizing radiation, and Cas9-induced chromosome breakage-promote nanotube-mediated DNA transfer in both cancerous and non-cancerous cells. Transferred DNA fragments are stably inherited as functional extrachromosomal genetic elements in the recipient host genome, thereby conferring heritable phenotypic traits to the recipient cell. Our findings uncover a horizontal gene transfer-like mechanism through which direct cell-cell contact can propagate genomic instability and reshape mammalian genomes.
Ho YH, Bregni G, Stazi M
… +23 more, Peinado P, Chen PH, Ballabio C, Boulat V, Vadera S, Guan Y, Liu Z, Alonso de la Vega A, Wang L, Ho CC, Veiga-Fernandes H, Downward J, Hsieh MS, Kopanitsa MV, Kassiotis G, Tsantoulas C, Schappe MS, Margineanu MB, Calado DP, Chiu IM, Swanton C, Chen JS, Li L
Sensory innervation regulates lung physiology and pathology, but its role in lung cancer is poorly understood. We show that lung adenocarcinoma (LUAD) progression locally amplifies nociceptive sensory innervation and act...Sensory innervation regulates lung physiology and pathology, but its role in lung cancer is poorly understood. We show that lung adenocarcinoma (LUAD) progression locally amplifies nociceptive sensory innervation and activation, which drives the release of a major sensory neuropeptide, calcitonin gene-related peptide (CGRP). CGRP acts on a subset of macrophages, thereby impairing the recruitment of CXCL13 fibroblasts and blocking tertiary lymphoid structure (TLS) assembly, a key predictor of LUAD prognosis. Local sensory denervation restores TLS formation, enhances B and T cell-dependent immunity, and suppresses tumor growth. Cigarette smoke extract (CSE) further activates this neural circuit to accelerate LUAD progression. In CSE-exposed animals, pharmacologic CGRP blockade sensitizes tumors to immunotherapy and prolongs survival. Together, our findings uncover a neuroimmune axis linking nociceptive neurons, TLS, and LUAD and identify neurogenic inflammation as a mechanism by which smoking promotes lung tumorigenesis independent of somatic mutagenesis.
Spermatogenesis features the seminiferous epithelial cycle, a periodic progression of germ-cell differentiation along the seminiferous tubules. Using seqFISH+ spatial transcriptomics, we profiled 2,653 genes in 867,062 m...Spermatogenesis features the seminiferous epithelial cycle, a periodic progression of germ-cell differentiation along the seminiferous tubules. Using seqFISH+ spatial transcriptomics, we profiled 2,653 genes in 867,062 mouse testis cells, revealing tubule-level transcriptional patterns that recapitulate the cycle and enable high-resolution temporal mapping of cells. Unlike other somatic cells, Sertoli cells exhibit a cyclic transcriptional profile synchronized with spermatogenesis. This cyclicity persists in germ-cell-depleted testes (busulfan and W/W), although with gene-specific dephasing and reduced amplitude, supporting an intrinsic Sertoli cyclic program. We identify retinoic acid (RA) as a permissive signal: germ-cell-depleted Sertoli cells cycle RA enzymes, while inhibiting RA synthesis via WIN 18,446 arrests them mid-cycle. Ligand-receptor analysis reveals bidirectional germ-Sertoli signaling. Notably, Wnt inhibition with LGK974 partially recapitulates germ-cell-depletion dephasing and amplitude changes. These findings support an integrative model where an intrinsic Sertoli program maintains baseline periodicity, while germ-cell signals refine the cycle to coordinate spermatogenesis.
Mammalian eyes are exposed to visible light but cannot perform photosynthesis. Here, we show that introducing a nanoscale, structurally and functionally preserved thylakoid system, LEAF (light-reaction enriched thylakoid...Mammalian eyes are exposed to visible light but cannot perform photosynthesis. Here, we show that introducing a nanoscale, structurally and functionally preserved thylakoid system, LEAF (light-reaction enriched thylakoid NADPH-foundry), into corneal cells enables light-driven bona fide photosynthetic production of NADPH and ATP, similar to plant leaves, which alleviates oxidative stress and inflammation. LEAF acts in two domains. Intracellularly, it integrates with host cells to supply NADPH and ATP via intact photosynthetic electron transport, restoring redox balance. Extracellularly, photosynthesized NADPH enhances endogeneous antioxidant enzyme activity and reduces reactive oxygen species in the local environment. These results establish a strategy for using light as an energy input in mammalian metabolic systems and suggest a possible cross-kingdom, endosymbiosis-like interaction in which animal cells derive functional benefits from plant-derived photosynthetic neo-organelles.
Bjelajac JR, Cañellas-Socias A, Nehra P
… +11 more, Reynolds K, Malipatlolla M, Martinez Velez N, Manjarrez DC, Ho K, Xu P, Hamad JL, Yamada-Hunter SA, Labanieh L, Sotillo E, Mackall CL
We sought to endow T cell autonomous regulation of cell surface protein expression by exploiting the conditional proteolytic activity of ADAM17 following T cell activation. Screening of canonical ADAM17 substrates yielde...We sought to endow T cell autonomous regulation of cell surface protein expression by exploiting the conditional proteolytic activity of ADAM17 following T cell activation. Screening of canonical ADAM17 substrates yielded a minimal 15-aa CD62L-derived motif that confers rapid and reversible cleavage of a receptor following T cell activation-termed activation-induced release (AIR). Embedding AIR into tonic-signaling CARs reduced basal CAR expression proportional to the degree of tonic signaling induced, curtailing exhaustion and improving antitumor potency. In non-tonic signaling CARs, AIR decreased activation-induced cell death and enhanced T cell expansion after stimulation. AIR's modularity supports higher-order logic-gating; AIR-regulated peptide masks enable antigen-dependent unmasking of an EGFR-targeting CAR. Finally, CRISPR knockin of AIR into endogenous FAS or TGFBR2 endowed them with activation-induced shedding, which enhanced tumor clearance while preserving signaling in non-activating conditions. AIR is a compact switch that provides fast, autonomous regulation of surface proteins for next-generation cell therapies.
Du S, Long Q, Zhou Y
… +34 more, Fu J, Wu H, Yang L, Xie Y, Ding Y, Zhang M, Guo J, Wang M, Lin J, Hu M, Zhang J, Yao D, Li W, Bao F, Xiang G, Wu Y, Huang Y, Liang H, Wang R, Li H, Chen B, Li C, Wang J, Zhang J, Qin D, Sun J, Zhu Y, Sun F, Wang W, Lu G, Chan WY, Zhao H, Liu C, Liu X
Despite extensive research, molecular differences in human populations and the influence of ancestry, age, geography, and diet are poorly understood. We performed comprehensive multiomics profiling (including genomics, t...Despite extensive research, molecular differences in human populations and the influence of ancestry, age, geography, and diet are poorly understood. We performed comprehensive multiomics profiling (including genomics, transcriptomics, proteomics, metabolomics, lipidomics, metallomics, glycomics, and microbiomics) on samples from 322 healthy individuals of European, East Asian, and South Asian ancestry across multiple continents. We identified ethnicity-associated molecular features linked to host metabolism, autoimmune disease risk, drug metabolism, and neurodegenerative pathways. We uncovered ancestry- and geography-related molecular changes affecting metabolism, immune function, microbiome composition, and biological aging. Specific genetic variants and gene expression differences were associated with lipid metabolism and immune regulation. Geography influenced biological age: East Asians showed lower biological age in their ancestral regions, whereas individuals of European ancestry exhibited lower biological age in the US/Canada than in Europe. Diet-microbiome metabolism interactions displayed ethnicity-specific patterns, many related to health. This open access resource advances understanding of ethnicity-environment interactions and supports precision medicine.
Antibody-drug conjugates are among the fastest-growing anticancer therapies, delivering potent payloads directly to tumor cells with improved safety across hematologic and solid tumors. This review focuses on their biolo...Antibody-drug conjugates are among the fastest-growing anticancer therapies, delivering potent payloads directly to tumor cells with improved safety across hematologic and solid tumors. This review focuses on their biology and where the field needs to move as they expand into earlier-stage use and combinations that heighten the need for careful patient selection and toxicity management.
Mitochondria generate phosphoenolpyruvate (PEP), although its export mechanism and physiological roles were unknown. In this issue of Cell, Kajimura and colleagues identify SLC25A35 as the mitochondrial PEP exporter and...Mitochondria generate phosphoenolpyruvate (PEP), although its export mechanism and physiological roles were unknown. In this issue of Cell, Kajimura and colleagues identify SLC25A35 as the mitochondrial PEP exporter and uncover a previously unrecognized role for mitochondrial PEP synthesis in glyceroneogenesis in adipose tissue and upon development of fatty liver disease.