eLife: latest articles by subject

Physiological febrile heat stress increases cytoadhesion through increased protein trafficking of Plasmodium falciparum surface proteins into the red blood cell

moritz.treeck@gimm.pt (David Anaguano) — Wed, 13 May 2026 00:00:00 +0000

Fever is a hallmark of malaria. Several studies have linked febrile temperatures to reduced parasite viability, but also to increased cytoadhesion, a key driver of pathology. However, different mechanisms have been proposed to cause changes in cytoadhesion and parasite sensitivity to heat. Here, we demonstrate that exposure of Plasmodium falciparum-infected red blood cells (iRBCs) to physiologically relevant febrile heat stress (39 °C), derived from patient data, enhances cytoadhesion through increased trafficking of the major virulence factor PfEMP1 to the iRBC surface. This phenomenon is not limited to PfEMP1 and common laboratory strains, as it extends to the surface nutrient channel PSAC in four clinical isolates of diverse geographic origin. The increased surface protein display occurs without changes in overall protein expression or parasite developmental progression. Using phosphoproteomics and proximity labelling, we find that elevated temperature also increases trafficking and phosphorylation of exported proteins into the RBC. Enhanced export is likely reliant on the presence of a transmembrane domain as shown by NanoLuc reporter assays. Collectively, our results indicate that febrile temperatures commonly experienced during infection can accelerate protein export, likely at the parasitophorous vacuole. This enhanced export following heat stress is relevant because increased cytoadhesion could influence disease severity through earlier iRBC sequestration and elevated bound parasite mass.

Examining the role of lipids in hearing

Angela.Ballesteros@nih.gov (Angela Ballesteros) — Wed, 13 May 2026 00:00:00 +0000

The asymmetry of lipid membranes is tightly regulated in eukaryotic cells, and auditory hair cells are no exception.

A novel 3D visualization method in mice identifies the periportal lamellar complex (PLC) as a key regulator of hepatic ductal and neuronal branching morphogenesis

chongchen@scu.edu.cn (Banglei Yin) — Thu, 07 May 2026 00:00:00 +0000

The liver is a complex organ responsible for multiple functions, including metabolism, energy storage, detoxification, bile secretion, and immune regulation. Its highly organized vascular system plays a crucial role in maintaining functional zonation and tissue homeostasis. Within the liver, the hepatic artery, portal vein, hepatic vein, bile duct, and nerve networks intertwine to form an intricate three-dimensional architecture; however, traditional two-dimensional imaging fails to reveal their true spatial relationships, and current three-dimensional imaging methods remain insufficient to capture fine structural details. To achieve comprehensive visualization of these multi-ductal systems, we established a high-resolution three-dimensional imaging platform that combines multicolor perfusion of metallic compound nanoparticles (MCNPs) with an optimized tissue-clearing protocol (Liver-CUBIC), enabling simultaneous 3D reconstruction of the portal vein, hepatic artery, bile duct, and hepatic vein in mouse livers. Based on these data, we identified and defined a previously unrecognized structure located in the outer layer of the portal vein, termed the periportal lamellar complex (PLC). The PLC encircles the portal vein between the vascular endothelium and the perisinusoidal region, exhibits low-permeability barrier characteristics, and contains a distinctive population of CD34⁺Sca-1⁺ endothelial cells. During liver fibrosis, the PLC extends from the portal vein toward the hepatic lobule, forming a structural scaffold that guides bile duct and nerve migration.

HER2-driven mammary tumorigenesis enhances bioenergetics despite reductions in mitochondrial content

sfrangos@uoguelph.ca (Cezar M Khursigara) — Wed, 06 May 2026 00:00:00 +0000

It is now recognized that mitochondria play a crucial role in tumorigenesis; however, it has become clear that tumor metabolism varies significantly between cancer types. The failure of recent clinical trials aimed at directly targeting tumor respiration through oxidative phosphorylation inhibitors underscores the critical need for further studies providing an in-depth evaluation of mitochondrial bioenergetics. Accordingly, we comprehensively assessed the bulk tumor and mitochondrial metabolic phenotype in murine HER2-driven mammary cancer tumors and benign mammary tissue. Transcriptomic and proteomic profiling revealed a broad downregulation of mitochondrial genes/proteins in tumors, including OXPHOS subunits comprising Complexes I–IV. Despite reductions in tumor mitochondrial proteins, mitochondrial respiration was several-fold higher compared to benign mammary tissue, which persisted regardless of normalization method (wet weight, total protein content, and when corrected for mitochondrial content). This upregulated respiratory capacity could not be explained by OXPHOS uncoupling, suggesting HER2 signaling regulates intrinsic mitochondrial bioenergetics. In further support, lapatinib, an EGFR/HER2 tyrosine kinase inhibitor, attenuated mitochondrial respiration in NF639 murine mammary tumor epithelial cells. Together, this data highlights that the typical correlation between mitochondrial content and respiratory capacity may not apply to all tumor types and implicates HER2-linked activation of mitochondrial respiration supporting tumorigenesis in this model.

Mitochondrial ETF insufficiency drives neoplastic growth by selectively optimizing cancer bioenergetics

david.papadopoli@mail.mcgill.ca (Daina Avizonis) — Tue, 05 May 2026 00:00:00 +0000

Mitochondrial electron transport flavoprotein (ETF) insufficiency causes metabolic diseases known as a multiple acyl-CoA dehydrogenase deficiency (MADD). In contrast to muscle, ETFDH is a non-essential gene in acute lymphoblastic leukemia NALM6 cells, and its expression is reduced across human cancers. In various human cancer cell lines and mouse models, ETF insufficiency caused by decreased ETFDH expression limits flexibility of OXPHOS fuel utilisation but paradoxically increases bioenergetics and accelerates neoplastic growth via activation of the mTORC1/BCL-6/4E-BP1 axis. Collectively, these findings reveal that while ETF insufficiency is rare and has detrimental effects in non-malignant tissues, it is common in neoplasia, where ETFDH downregulation leads to bioenergetic and signaling reprogramming that accelerates neoplastic growth.

Prickle and Ror modulate Dishevelled-Vangl interaction to regulate non-canonical Wnt signaling during convergent extension in Xenopus

j18wang@uab.edu (Allyson R Angermeier) — Thu, 30 Apr 2026 00:00:00 +0000

Convergent extension (CE) is a fundamental morphogenetic process where oriented cell behaviors lead to polarized extension of diverse tissues. In vertebrates, regulation of CE requires both non-canonical Wnt, its co-receptor Ror, and several ‘core members’ of the planar cell polarity (PCP) pathway. PCP was originally identified as a mechanism to coordinate the cellular polarity in the plane of static epithelium, where core proteins Frizzled (Fz)/Dishevelled (Dvl) and Van Gogh-like (Vangl)/Prickle (Pk) partition to opposing cell cortex. But how core PCP proteins interact with each other to mediate non-canonical Wnt/Ror signaling during CE is not clear. We found previously that during CE, Vangl cell-autonomously recruits Dvl to the plasma membrane and keeps Dvl inactive. In this study, we show that non-canonical Wnt induces Dvl to transition from Vangl to Fz in Xenopus embryos. Pk inhibits the transition and functionally synergizes with Vangl to suppress Dvl during CE. Conversely, Ror is required for the transition and functionally antagonizes Vangl. Biochemically, Vangl interacts directly with both Ror and Dvl. Ror and Dvl do not bind directly but can be co-fractionated with Vangl. Collectively, we propose that Pk assists Vangl to function as an unconventional adaptor that brings Dvl and Ror into a complex to serve two functions: (1) simultaneously preventing both Dvl and Ror from ectopically activating non-canonical Wnt signaling; and (2) relaying Dvl to Fz for signaling activation upon non-canonical Wnt-induced dimerization of Fz and Ror.

The FAM53C/DYRK1A axis regulates the G1/S transition of the cell cycle

julsage@stanford.edu (Anca M Pasca) — Thu, 30 Apr 2026 00:00:00 +0000

A growing number of therapies are being developed to target the cell cycle machinery for the treatment of cancer and other human diseases. Consequently, a greater understanding of the factors regulating cell cycle progression becomes essential to help enhance the response to these new therapies. Here, using data from the Cancer Dependency Map, we identified FAM53C as a new regulator of cell cycle progression. We found that FAM53C is critical for this cell cycle transition and that it acts upstream of the Cyclin D-CDK4/6-RB axis and of p53 in the regulation of the G1/S transition. By mass spectrometry, biochemical, and cellular assays, we identified and validated DYRK1A as a cell cycle kinase that is inhibited by and directly interacts with FAM53C. Consistent with the role for FAM53C identified in cells in culture, FAM53C knockout human cortical organoids display increased cell cycle arrest and growth defects. Fam53C knockout mice show minor behavioral phenotypes. Because DYRK1A dysregulation contributes to developmental disorders such as Down syndrome as well as tumorigenesis, future strategies aiming at regulating FAM53C activity may benefit a broad range of patients.

Unbend, correction of local beam-induced sample motion in cryo-EM images using a 3D spline model

lingli.kong1@umassmed.edu (Johannes Elferich) — Thu, 30 Apr 2026 00:00:00 +0000

The exposure of frozen biological samples to the high-energy electron beam in a cryo-electron microscope commonly leads to beam-induced sample motion and distortions. Previously, we described Unblur, software to correct for beam-induced motion based on the alignment of full frames in a movie collected during the beam exposure (Grant and Grigorieff, 2015). Here, we present Unbend, extending Unblur by accommodating more localized sample bending and distortions using a 3D cubic B-spline model. Unbend is integrated into our cisTEM software with a new local motion visualization panel. We processed movie frames from various in situ sample types, including whole cells, lamellae, and cell lysates, to analyze motion behavior across different specimen types. To quantify the improvement in high-resolution signal, we utilized the 2D template matching method to search large ribosomal subunits from the motion-corrected micrographs. Overall, the signal-to-noise ratio of detected particles improved by 3–8% across different samples compared with full-frame aligned micrographs, while the number of detected target particles increased by up to ~300%. Furthermore, we processed micrograph montages to study motion patterns across an entire sample, revealing considerable variance in distortion scale within the same sample, suggesting a complex underlying mechanism.

Single-cell lineage tracing identifies hemogenic endothelial cells in the adult mouse bone marrow

jingxinfeng475@gmail.com (Avinash Bhandoola) — Mon, 27 Apr 2026 00:00:00 +0000

During mouse development, hematopoietic stem and progenitor cells (HSPCs) originate from hemogenic endothelial cells (ECs) through a process of endothelial-to-hematopoietic transition. These HSPCs are thought to fully sustain adult hematopoiesis. However, it remains unknown whether adult ECs retain hemogenic potential. Here, we used in vivo genetic lineage tracking at population and single-cell (sc) levels, scRNA sequencing, and bone marrow (BM) transplantation to detect hemogenic ECs in adult mice. We identify and characterize BM-resident, adult Cdh5/VE-Cadherin⁺ ECs that produce hematopoietic cell-progeny in vitro and in mice. These adult hemogenic ECs and their hematopoietic cell progeny give rise to hematopoietic cells following adoptive transfer into adult mice. Furthermore, blood cells generated from adult and developmental ECs comparably home to peripheral tissues, where they similarly contribute to inflammatory responses. Thus, our results identify previously unrecognized BM-derived adult hemogenic ECs that generate HSPC and functional mature blood cells.

Clathrin-independent endocytosis and retrograde transport in cancer cells tune immune synapse organization and CD8 T cell response

henri-francois.renard@unamur.be (Alix Buridant) — Wed, 22 Apr 2026 00:00:00 +0000

Endophilin A3-mediated clathrin-independent endocytosis (EndoA3-mediated CIE) contributes to the internalization of immunoglobulin-like proteins, including key immune synapse components. Here, we identify ICAM1 as a novel EndoA3-dependent cargo, alongside ALCAM. We demonstrate that both proteins subsequently follow retromer-dependent retrograde transport to the trans-Golgi network (TGN) in cancer cells. From there, we propose that they undergo polarized redistribution to the plasma membrane, where they contribute to immune synapse formation between cancer cells and cytotoxic CD8 T cells. Disruption of EndoA3 or retromer components significantly affects the response of autologous cytotoxic CD8 T cells, as evidenced by reduced cytokine production and secretion, but increased lytic activity, while proliferation and later activation marker expression remain intact. This is accompanied by diminished ICAM1 density at the immune synapse, where we observe it arriving via polarized vesicular transport, indicating altered synapse organization. Indeed, cancer cells lacking EndoA3-mediated CIE or retromer form enlarged immune synapses that fail to sustain full T cell cytokine secretion, suggesting a compensatory attempt by T cells to overcome the defective synapse, while likely promoting more transient contacts that potentially favor serial killing. Together, these findings reveal that EndoA3-mediated CIE and retrograde transport act in concert in cancer cells to relocate immune synapse components via the Golgi, thereby fine-tuning the balance between cytotoxic T cell cytokine secretion and lytic activity. These insights contribute to a better understanding of the mechanisms governing immune synapse formation and organization, providing a necessary foundation for the long-term identification of new strategies to enhance T cell–mediated anti-tumor immunity.

Prior cocaine use disrupts identification of hidden states by single units and neural ensembles in orbitofrontal cortex

wenhui.zong@nih.gov (Geoffrey Schoenbaum) — Tue, 21 Apr 2026 00:00:00 +0000

The orbitofrontal cortex (OFC) is critical to identifying task structure and to generalizing appropriately across task states with similar underlying or hidden causes. This capability is at the heart of OFCs proposed role in a network responsible for cognitive mapping, and its loss can explain many deficits associated with OFC damage or inactivation. Substance use disorder is defined by behaviors that share much in common with these deficits, such as an inability to modify learned behaviors in the face of new information about undesired consequences. One explanation for this similarity would be if addictive drugs impacted the ability of OFC to recognize underlying similarities, hidden states, that allow information learned in one setting to be used in another. To explore this possibility, we trained rats to self-administer cocaine and then recorded single-unit activity in lateral OFC as these rats performed in an odor sequence task consisting of unique and shared positions. In well-trained controls, we observed chance decoding of sequence at shared positions and near chance decoding even at unique positions, reflecting the irrelevance of distinguishing these positions in the task. By contrast, in cocaine-experienced rats, decoding remained significantly elevated, particularly at the positions that had superficial sensory differences that were collapsed in controls across learning. These neural differences were accompanied by increases in behavioral variability at these positions. A tensor component analysis showed that this effect of reduced generalization after cocaine use also extended across positions in the sequences. These results show that prior cocaine use disrupts the normal identification of hidden states by OFC.

Orderly mitosis shapes interphase genome architecture

mistelit@mail.nih.gov (Adib Keikhosravi) — Tue, 21 Apr 2026 00:00:00 +0000

Genomes assume a complex 3D architecture in the interphase cell nucleus. Yet the molecular mechanisms that determine global genome architecture are only poorly understood. To identify mechanisms of higher-order genome organization, we performed high-throughput imaging-based CRISPR knockout screens targeting 1064 genes encoding nuclear proteins in multiple human cell lines. We assessed changes in the distribution of centromeres at single-cell resolution as surrogate markers for global genome organization. The screens revealed multiple major regulators of spatial distribution of centromeres, including components of the nucleolus, kinetochore, cohesins, condensins, and the nuclear pore complex. Alterations in centromere distribution required progression through the cell cycle and acute depletion of mitotic factors with distinct functions altered centromere distribution in the subsequent interphase. These results identify molecular determinants of spatial centromere organization, and they show that orderly progression through mitosis shapes interphase genome architecture.

Uncovering shared and tissue-specific molecular adaptations to intermittent fasting in liver, brain, and muscle

jayanthag@imcb.a-star.edu.sg (Christopher G Sobey) — Fri, 17 Apr 2026 00:00:00 +0000

Intermittent fasting (IF) has emerged as a powerful dietary intervention with profound metabolic benefits, yet the tissue-specific molecular mechanisms underlying these effects remain poorly understood. In this study, we employed comprehensive proteomics and transcriptomics analysis to investigate the systemic and organ-specific adaptations to IF in male C57BL/6 mice. Following a 16 hr daily fasting regimen (IF16) over 4 months, IF reduced blood glucose, HbA1c, and cholesterol levels while increasing ketone bodies, indicative of enhanced metabolic flexibility. Proteomic profiling of the liver, skeletal muscle, and cerebral cortex revealed tissue-specific responses, with the liver exhibiting the most pronounced changes, including upregulation of pathways involved in fatty acid oxidation, ketogenesis, and glycan degradation, and downregulation of steroid hormone and cholesterol metabolism. In muscle, IF enhanced pyruvate metabolism, fatty acid biosynthesis, and AMPK signaling, while suppressing oxidative phosphorylation and thermogenesis. The cerebral cortex displayed unique adaptations, with upregulation of autophagy, PPAR signaling, and metabolic pathways, and downregulation of TGF-beta and p53 signaling, suggesting a shift toward energy conservation and stress resilience. Notably, Serpin A1c emerged as the only protein commonly upregulated across all three tissues, highlighting its potential role in systemic adaptation to IF. Integrative transcriptomic and proteomic analyses revealed partial concordance between mRNA and protein expression, underscoring the complexity of post-transcriptional regulation. Shared biological signaling processes were identified across tissues, suggesting unifying mechanisms linking metabolic changes to cellular communication. Our findings reveal both conserved and tissue-specific responses by which IF may optimize energy utilization, enhance metabolic flexibility, and promote cellular resilience.

Kinesin-1 conformational dynamics are controlled by a cargo-sensitive TPR switch

jj.phillips@exeter.ac.uk (Christiane Schaffitzel) — Tue, 14 Apr 2026 00:00:00 +0000

Kinesin-1 is a dynamic heterotetrameric assembly of two heavy and two light chains (KHC and KLC) that mediates microtubule-based intracellular transport of many different cargoes. The complex adopts a compact, autoinhibited state that is activated by cargo-adaptor proteins containing specific short linear peptide motifs (SLiMs). These motifs interact with the tetratricopeptide repeat (TPR) domains of the KLCs. The mechanism coupling SLiM recognition to activation-associated conformational changes in the complex is unknown. Here, we combine protein design, computational modelling, biophysical analysis, and electron microscopy to examine the structural and mechanistic consequences of SLiM binding to the KLC-TPR domain within the complete heterotetrameric holoenzyme. We show that coiled coil 1 (CC1) of the KHC docks KLC TPR domains in the autoinhibited complex, forming the ‘shoulder’ feature observed in electron microscopy. Disrupting this interaction or binding an activating SLiM dislocates the TPR shoulder, freeing the motor domains and promoting transition between its closed, inactive, and open states. Opening the kinesin-1 complex facilitates binding to the microtubule-associated kinesin-1 cofactor, microtubule-associated protein 7 (MAP7). Therefore, cargo-mediated dislocation of the TPR shoulder serves as a key initial step in kinesin-1 activation, allosterically linking cargo binding to motor dynamics.

GTPase-activating protein DLC1 spatio-temporally regulates Rho signaling

olivier.pertz@unibe.ch (Giliane Rochat) — Fri, 10 Apr 2026 00:00:00 +0000

Emerging evidence suggests that Guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) bind to the cytoskeleton or focal adhesions (FAs), controlling spatio-temporal Rho GTPase activity through feedback mechanisms. We explore such feedback in the Rho-specific GAP Deleted in Liver Cancer 1 (DLC1), which binds to FAs through mechanosensitive interactions. Using a FRET biosensor, we show that DLC1 loss of function leads to globally increased Rho activity and contractility in fibroblasts. Although Rho activity appears macroscopically steady, individual molecules undergo ‘signaling flux’—a dynamic cycle of activation and deactivation. To measure this flux, we built a genetic circuit that enables both optogenetic activation of Rho and simultaneous readout of Rho activity. In cells at mechanical steady state, this reveals that DLC1 globally controls the rate of Rho deactivation, both at FAs and at the plasma membrane. Transient induction of local contractility, however, shows DLC1 associating with and dissociating from FAs during their reinforcement and relaxation, which might provide local positive feedback on Rho activity for robust FA disassembly. Together, our results indicate that DLC1 regulates Rho activity both globally at steady state and locally at FAs under tension, highlighting the complexity of spatio-temporal Rho GTPase signaling.

Specialisation of meiotic kinetochores revealed through a synthetic spindle assembly checkpoint strategy

adele.marston@ed.ac.uk (Adèle L Marston) — Thu, 09 Apr 2026 00:00:00 +0000

Meiosis creates haploid gametes through two sequential M phases. While many studies have focused on meiosis I, the molecular events which drive and define meiosis II are largely unknown. Here, we report a novel cell synchronisation strategy which allows for collection of budding yeast Saccharomyces cerevisiae cells arrested at metaphase I or metaphase II, enabling better characterisation of meiosis II events. The method relies on chemically-inducible dimerisation of ectopic copies of spindle assembly checkpoint (SAC) proteins Mps1 and Spc105. Using this synthetic SAC (SynSAC) approach, we found that the SAC response is weaker in metaphase I compared to metaphase II and that the PP1 binding site within Spc105 contributes to restraining the MI SAC response. Furthermore, we demonstrate the utility of the SynSAC approach by analysing the composition and phosphorylation of kinetochores from metaphase I and metaphase II. This revealed an increase in the abundance of outer kinetochore proteins in meiotic metaphase I and reduced phosphorylation on metaphase II kinetochore proteins. Overall, we present the SynSAC method as a valuable tool for analysis of both meiotic metaphases.

Probing metazoan polyphosphate biology using Drosophila reveals novel and conserved polyP functions

rashna@cdfd.org.in (Deepa Balasubramanian) — Wed, 08 Apr 2026 00:00:00 +0000

Polyphosphate (polyP) exists in all life forms; however, its biological functions in metazoans are understudied. Here, we explored Drosophila, to our knowledge, as the first genetic model to explore polyP biology in metazoans. We established biochemical and in situ methods to detect, quantify, and visualise polyP in Drosophila. We then engineered a FLYX system to deplete polyP in subcellular compartments in a tissue-specific manner. Using these tools, we demonstrated a spatiotemporal and subcellular compartment-specific regulation of polyP levels in various developmental stages and tissue types. We discovered that polyP is crucial for Drosophila hemolymph clotting and proper developmental timing, consistent with an evolutionarily conserved role as exogenous polyP also accelerates mammalian blood clotting. Furthermore, the transcriptomics analysis of polyP-depleted larvae demonstrates the impact of polyP on several cellular processes, including translation. These observations underscore the utility of the toolkit we developed to discover previously unknown polyP functions in metazoans.

Extracellular vesicle-mediated release of bis(monoacylglycerol)phosphate is regulated by LRRK2 and glucocerebrosidase activity

kalpana.merchant@northwestern.edu (Albert Lu) — Thu, 02 Apr 2026 00:00:00 +0000

The endolysosomal phospholipid bis(monoacylglycerol)phosphate (BMP) is aberrantly elevated in urine from Parkinson’s patients carrying mutations in leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GCase). Because BMP resides on, and regulates biogenesis of, endolysosomal intralumenal membranes that become extracellular vesicles (EVs) upon release, we hypothesized that increased urinary BMP reflects enhanced exocytosis of BMP-enriched EVs. We analyzed BMP metabolism and EV-associated BMP release in wild-type (WT) and R1441G LRRK2 mouse embryonic fibroblasts (MEFs). Immunofluorescence and transmission electron microscopy revealed structural alterations in endolysosomes and the antibody-accessible BMP pool, indicating disrupted endolysosomal homeostasis. Biochemical analysis of isolated EV fractions showed increased release of LAMP2-positive EVs by mutant cells, partially restored by LRRK2 kinase inhibition but further, variably, increased by GCase inhibition. Mass spectrometry detected higher total di-22:6-BMP and di-18:1-BMP in mutant LRRK2 MEFs compared to WT. Inhibition of LRRK2 partially restored cellular BMP, whereas GCase inhibition further elevated it. In EVs from mutant cells, LRRK2 inhibition reduced BMP content, while GCase inhibition tended to increase it. Metabolic labeling showed elevated BMP was not due to increased synthesis, despite higher levels of the BMP-synthesizing enzyme CLN5 in mutant MEFs and patient fibroblasts. Finally, pharmacological modulation of EV release and live total internal reflection fluorescence imaging in human G2019S LRRK2 fibroblasts further confirmed that BMP release is likely associated with EV secretion. Together, these results establish LRRK2 as a regulator of BMP in cells and its release through EVs and suggest that GCase activity further modulates this process in LRRK2 mutant cells. Mechanistic insights from these studies have implications for the use of BMP-positive EVs as potential biomarkers for Parkinson’s disease.

Human receptive endometrial assembloid for deciphering the implantation window

chenzijiang@hotmail.com (Boyang Liu) — Wed, 01 Apr 2026 00:00:00 +0000

Human endometrial receptivity is a critical determinant of pregnancy success; however, in vivo studies of its features and regulation are particularly challenging due to ethical restrictions. Recently, the development of human endometrial assembloids has provided a powerful model to investigate this intricate biological process. In this study, we established a specialized human window-of-implantation (WOI) endometrial assembloid system that mimics the in vivo receptive endometrium. It not only reproduces the structural attributes of pinopodes and cilia, but also molecular characteristics of mid-secretory endometrium. Furthermore, the WOI endometrial assembloid exhibits hormone responsiveness, an energy metabolism profile characterized by larger and functionally enhanced mitochondria, increased ciliary assembly and motility, and epithelial-mesenchymal transition (EMT), as well as promising potential for embryo implantation. As such, WOI assembloids hold great promise as a platform to unravel the intricate mechanisms governing the regulation of endometrial receptivity, maternal-fetal interactions, and associated pathologies, ultimately driving impactful advancements in the field.

Death receptor 6 does not regulate axon degeneration and Schwann cell injury responses during Wallerian degeneration

bogdan.beirowski@osumc.edu (Bogdan Beirowski) — Fri, 27 Mar 2026 00:00:00 +0000

Axon degeneration (AxD), accompanied by glial remodeling, is a pathological hallmark of many neurodegenerative diseases, leading to the disruption of neuronal connectivity. Understanding the mechanisms in neurons and glia that regulate AxD is essential for developing therapeutic strategies to prevent or mitigate axon loss. Wallerian degeneration (WD) is a well-established model to study the mechanisms of nerve injury-induced AxD, glial responses, and axon-glia interactions. We recently showed that Schwann cells (SCs), the axon-associated glia of the peripheral nervous system, exert protective effects on axons through their rapid metabolic injury response. Enhancing this SC response promotes axon protection during WD. A prior study reported that eliminating the orphan tumor necrosis factor receptor DR6 (death receptor 6, encoded by Tnfrsf21) strongly delays AxD and alters SC injury responses during WD, suggesting a possible intersection with our findings. Here, we rigorously revisit the role of DR6 in WD using two independent DR6 knockout mouse lines including the same model used in the previous study. Surprisingly, in contrast to the earlier report, we observed no impact of DR6 deletion on AxD kinetics or SC injury responses across a range of WD assays. Moreover, injured axons in primary neuronal cultures lacking DR6 degenerated at a similar rate as wild-type axons. We conclude that DR6 is dispensable for the regulation of AxD and glial nerve injury responses during WD. Our data argue that any therapeutic benefit from DR6 suppression in neurodegeneration models occurs through mechanisms independent of WD.

Age-dependent H3K9 trimethylation by dSetdb1 impairs mitochondrial UPR leading to degeneration of olfactory neurons and loss of olfactory function in Drosophila

mario.sanhueza@umayor.cl (Felipe A Court) — Thu, 26 Mar 2026 00:00:00 +0000

Aging is characterized by a decline in essential sensory functions, including olfaction, which is crucial for environmental interaction and survival. This decline is often paralleled by the cellular accumulation of dysfunctional mitochondria, particularly detrimental in post-mitotic cells, such as neurons. Mitochondrial stress triggers the mitochondrial unfolded protein response (UPR^MT), a pathway that activates mitochondrial chaperones and antioxidant enzymes. Critical to the efficacy of the UPR^MT is the cellular chromatin state, influenced by the methylation of lysine 9 on histone 3 (H3K9). While it has been observed that the UPR^MT response can diminish with an increase in H3K9 methylation, its direct impact on age-related neurodegenerative processes, especially in the context of olfactory function, has not been clearly established. Using Drosophila, we demonstrate that an age-dependent increase in H3K9 trimethylation by the methyltransferase dSetdb1 reduces the activation capacity of the UPR^MT in olfactory projection neurons, leading to neurodegeneration and loss of olfactory function. Age-related neuronal degeneration was associated with morphological alterations in mitochondria and an increase in reactive oxygen species levels. Importantly, forced demethylation of H3K9 through knockdown of dSetdb1 in olfactory projection neurons restored the UPR^MT activation capacity in aged flies, and suppressed age-related mitochondrial morphological abnormalities. This, in turn, prevented age-associated neuronal degeneration and rescued age-dependent loss of olfactory function. Our findings highlight the effect of age-related epigenetic changes on the response capacity of the UPR^MT, impacting neuronal integrity and function. Moreover, they suggest a potential therapeutic role for UPR^MT regulators in age-related neurodegeneration and loss of olfactory function.

Uev1A counteracts oncogenic Ras stimuli in both polyploid and diploid cells

hrzhang@nankai.edu.cn (Dongze Song) — Wed, 25 Mar 2026 00:00:00 +0000

Oncogenic Ras is known to induce DNA replication stress, leading to cellular senescence or death. In contrast, we found that it can also trigger polyploid Drosophila ovarian nurse cells to die by inducing aberrant division stress. To explore intrinsic protective mechanisms against this specific form of cellular stress, here, we conducted a genome-wide genetic screen and identified the E2 enzyme Uev1A as a key protector. Reducing its expression levels exacerbates the nurse cell death induced by oncogenic Ras, while overexpressing it or its human homologs, UBE2V1 and UBE2V2, mitigates this effect. Although Uev1A is primarily known for its non-proteolytic functions, our studies demonstrate that it collaborates with the E3 APC/C complex to mediate the proteasomal degradation of Cyclin A, a key cyclin that drives cell division. Furthermore, Uev1A and UBE2V1/2 also counteract oncogenic Ras-driven tumorigenesis in diploid cells, suppressing the overgrowth of germline tumors in Drosophila and human colorectal tumor xenografts in nude mice, respectively. Remarkably, elevated expression levels of UBE2V1/2 correlate with improved survival rates in human colorectal cancer patients harboring oncogenic KRAS mutations, indicating that their upregulation could represent a promising therapeutic strategy.

Human dynein–dynactin is a fast processive motor in living cells

patw@bio.umass.edu (Patricia Wadsworth) — Wed, 25 Mar 2026 00:00:00 +0000

Minus-end directed transport along microtubules in eukaryotes is primarily mediated by cytoplasmic dynein and its cofactor dynactin. Significant advances have been made in recent years characterizing human dynein–dynactin structure and function using in vitro assays; however, there is limited knowledge about the motile properties and functional organization of dynein–dynactin in living human cells. Total internal reflection fluorescence microscopy of CRISPR-engineered human cells is employed here to visualize fluorescently tagged dynein heavy chain (DHC) and p50 with high spatio-temporal resolution. We find that p50 and DHC exhibit indistinguishable motility properties in their velocities, run lengths, and run times. The dynein–dynactin complexes are fast (~1.2 µm/s) and run for several microns (~2.7 µm). Quantification of the fluorescence intensities of motile puncta reveals that dynein–dynactin runs are mediated by at least one DHC dimer while the velocity is consistent with that measured for double dynein (two DHC dimers) complexes in vitro.

Specific GPCRs elicit unique extracellular vesicle miRNA array signatures

shixiaosmile@yahoo.com (Aaron J Janowsky) — Fri, 20 Mar 2026 00:00:00 +0000

All cells secrete extracellular vesicles (EVs) containing nucleic acid cargo, including microRNAs (miRNAs), that regulate the function of receiving cells. G protein-coupled receptors (GPCRs) affect intracellular function via multiple signaling cascades. However, the mechanisms of GPCR intercellular signaling through EV miRNA activity remain unknown. Human U2 osteosarcoma cells expressing native GPCRs were used to selectively stimulate distinct G protein signaling cascades (Gα_i, Gα_q, Gα_12/13, and β-arrestin) by members of specific receptor subclasses, including the adenosine receptor A1 (ADORA1), the histamine receptor H1 (HRH1), the frizzled class receptor 4 (FZD4), and the atypical chemokine receptor 3 (ACKR3), respectively. We hypothesized that stimulation of specific classes of GPCRs would cause the release of EVs containing miRNAs with receptor-specific up- or downregulated expression, affecting unique pathological downstream signaling cascades. Receptor-specific agonists dose-dependently increased respective signaling cascade intermediates. We found no change in the quantity of EVs (~200 nm diameter), but there were distinct EV miRNA signatures following stimulation of GPCRs. Network analyses of differentially expressed miRNA and their predicted targets validated the linkage between specific receptors and cell function and pathological states. The data can be used to reverse engineer mechanisms involving EV miRNAs for various physiological and pathological processes. GPCRs are major pharmacological targets, so understanding the mechanisms that stimulate or inhibit GPCR-mediated changes in extracellular miRNA signatures could improve long- and short-term therapeutic and unwanted drug effects.

Large-scale identification of plasma membrane repair proteins revealed spatiotemporal cellular responses to plasma membrane damage

keiko.kono@oist.jp (Keiko Kono) — Tue, 10 Mar 2026 00:00:00 +0000

Damage to the plasma membrane (PM) is common in all types of cells. PM repair processes, including exocytosis and endocytosis, are not mutually exclusive; rather, they collaborate to repair the wound. However, the temporal coordination between the repair processes remains poorly understood. Here, by large-scale identification and live-cell imaging of PM repair proteins, we analyzed the spatiotemporal PM damage responses in Saccharomyces cerevisiae. Of the 80 repair proteins identified, 72 proteins were previously unreported repair protein candidates. Among the observed repair processes, the polarized exocytosis and clathrin-mediated endocytosis (CME) are coupled at the damage site, with exocytosis predominating in the early stage of PM repair and CME predominating in the late stage of PM repair. Furthermore, we showed that CME at the growing bud site directs PM repair proteins with transmembrane domains to the damage site. We propose a model in which CME delivers repair proteins with transmembrane domains between the growing bud site and the damage site. This study provides a functional catalog of PM repair proteins and insights into spatiotemporal cellular responses to PM damage.

Cardiac neurons expressing a glucagon-like receptor mediate cardiac arrhythmia induced by high-fat diet in Drosophila

zhan@som.umaryland.edu (Jianli Duan) — Fri, 06 Mar 2026 00:00:00 +0000

Cardiac arrhythmia leads to increased risks for stroke, heart failure, and cardiac arrest. Arrhythmic pathology is often rooted in the cardiac conduction system, but the mechanism is complex and not fully understood. For example, how metabolic diseases, like obesity and diabetes, increase the risk for cardiac arrhythmia. Glucagon regulates glucose production, mobilizes lipids from the fat body, and affects cardiac rate and rhythm, attributes of a likely key player. Drosophila is an established model to study metabolic diseases and cardiac arrhythmias. Since glucagon signaling is highly conserved, we used high-fat diet (HFD)-fed flies to study its effect on heart function. HFD led to increased heartbeat and an irregular rhythm. The HFD-fed flies showed increased levels of adipokinetic hormone (Akh), the functional equivalent to human glucagon. Both genetic reduction of Akh and eliminating the Akh-producing cells (APC) rescued HFD-induced arrhythmia, whereas heart rhythm was normal in Akh receptor mutants (AkhR^null). Furthermore, we discovered a pair of cardiac neurons that express high levels of Akh receptor. These are located near the posterior heart, make synaptic connections at the heart muscle, and regulate heart rhythm. Altogether, this Akh signaling pathway provides new understanding of the regulatory mechanisms between metabolic disease and cardiac arrhythmia.

Correction: Opposing p53 and mTOR/AKT promote an in vivo switch from apoptosis to senescence upon telomere shortening in zebrafish

Wed, 04 Mar 2026 00:00:00 +0000

SLC4A1 mutations that cause distal renal tubular acidosis alter cytoplasmic pH and cellular autophagy

cordat@ualberta.ca (Emmanuelle Cordat) — Wed, 04 Mar 2026 00:00:00 +0000

Distal renal tubular acidosis (dRTA) is a disorder characterized by the inability of the collecting duct system to secrete acids during metabolic acidosis. The pathophysiology of dominant or recessive SLC4A1 variant-related dRTA has been linked with the mis-trafficking defect of mutant kAE1 protein. However, in vivo studies in kAE1 R607H dRTA mice and humans have revealed a complex pathophysiology implicating a loss of kAE1-expressing intercalated cells and intracellular relocation of the H⁺-ATPase in the remaining type-A intercalated cells. These cells also displayed accumulation of ubiquitin and p62 autophagy markers. The highly active transport properties of collecting duct cells require the maintenance of cellular energy and homeostasis, a process dependent on intracellular pH. Therefore, we hypothesized that the expression of dRTA variants affects intracellular pH and autophagy pathways. In this study, we report the characterization of newly identified dRTA variants and provide evidence of abnormal autophagy and degradative pathways in mouse inner medullary collecting duct cells and kidneys from mice expressing kAE1 R607H dRTA mutant protein. We show that reduced transport activity of the kAE1 variants correlated with increased cytosolic pH, reduced ATP synthesis, attenuated downstream autophagic pathways pertaining to the fusion of autophagosomes and lysosomes and/or lysosomal degradative activity. Our study elucidated a close relationship between the expression of defective kAE1 proteins, reduced mitochondrial activity, and decreased autophagy and protein degradative flux.