Ethnopharmacological relevance Despite its long history of use in traditional medicine for joint disorders, Wutou Decoction (WTD) has not been widely adopted as a complementary therapy for rheumatoid arthritis (RA) in modern practice. This is primarily due to a lack of robust pharmacological evidence and a clear understanding of its mechanisms of action. Further investigation into the mechanistic basis of WTD is essential to validate its efficacy and safety in the treatment of RA. Aim of the study Fibroblast-like synoviocytes in rheumatoid arthritis (RA-FLS) display a highly invasive phenotype, contributing to progressive bone and cartilage destruction. Evidence suggests that crosstalk between the hypoxic microenvironment and the Notch signaling pathway plays a central role in driving this pathological behavior, highlighting both as potential therapeutic targets. This study aimed to determine whether WTD exerts its therapeutic effect on RA by disrupting hypoxia-induced activation of the Notch signaling pathway. Materials and methods A collagen-induced arthritis (CIA) model in rats and hypoxia-treated RA-FLS were employed. WTD used in this study consist of Aconitum carmichaelii Debeaux. (processed root, 6 g), Astragalus mongholicus Bunge. (root, 9 g), Ephedra sinica Stapf. (herbaceous stem, 9 g), Paeonia lactiflora Pall. (root, 9 g) and Glycyrrhiza uralensis Fisch. (root, 9 g). The anti-arthritic effects of WTD were assessed through arthritis scoring, spleen index, and hematoxylin-eosin staining and Safranin O/Fast Green). The involvement of the Notch pathway and invasive RA-FLS phenotype was evaluated by immunostaining, RT-qPCR, and western blotting. Results WTD significantly attenuated synovial hyperplasia and cartilage degradation in CIA rats. In both CIA rat synovium and hypoxia-treated RA-FLS, WTD markedly inhibited activation of the HIF and Notch signaling pathways, along with the expression of their downstream target genes. Further analyses revealed that WTD suppressed hypoxia-induced RA-FLS invasiveness, including cartilage matrix degradation and pro-angiogenic activities, by blocking Notch signaling. Molecular docking suggested that active compounds in WTD may bind to the negative regulatory region domain of Notch receptors. Notably, WTD also reversed the hypoxia response induced by forced activation of the Notch pathway. Conclusions These findings elucidate the mechanism by which WTD alleviates RA, firstly demonstrating that it effectively inhibits the hypoxia-induced invasive phenotype of RA-FLS by targeting the Notch signaling pathway. However, this study has several limitations: the findings are based on a single batch of WTD, the predicted binding of active compounds to Notch receptors has not been experimentally validated, and the individual contributions of the candidate quality markers to the overall therapeutic effect remain to be systematically determined.

Pupillary block in PACG impedes aqueous humor (AH) flow through the iris–lens channel (ILC), while existing models that simplify the ILC geometry fail to accurately capture this flow and its role in PACG pathophysiology. A computational model is developed to investigate AH flow in the anterior segment of the human eye, in which the ILC is represented as a porous medium with variable porosity to account for different ILC conditions. The ILC is modeled as an equivalent porous medium to represent effective flow resistance rather than a physiological porous structure. The governing flow and solid mechanics equations are solved to systematically examine the effects of pupillary block severity on AH flow, pressure distribution, iris deformation, and energy dissipation. The results demonstrate that ILC porosity plays a critical role in determining the severity of pupillary block and the extent of anterior chamber angle (ACA) closure. When the porosity decreases below 0.35, the posterior–anterior pressure difference increases sharply to 419.14 Pa, driving anterior iris displacement and subsequent contact with the trabecular meshwork, thereby inducing ACA closure and increasing flow resistance and energy dissipation. In contrast, for porosities above 0.35, iris deformation is reduced by up to 67%, the ACA remains open, and AH flows smoothly, indicating a significantly alleviated pupillary block condition. This study provides new insight into the role of the ILC in pupillary block and suggests a novel therapeutic strategy based on modulation of ILC porosity to improve AH dynamics in PACG.

Lung microenvironment controls the homeostasis and function of alveolar macrophages (AMs), the major regulators of lung immunity, but the underlying mechanisms, particularly the role of microbiota, remain unclear. Here, with Lyz2creEi24fl/fl mice, we report that EI24 deficiency in macrophages disrupts AMs homeostasis but enhances their phagocytosis and inflammatory responses via metabolic rewiring. Consequently, Lyz2creEi24fl/fl mice exhibit resistance to viral infection and tumor metastasis in lung. Notably, EI24 expression in AMs is upregulated by commensal microbiota through TLR2/4 signaling. These data demonstrate that microbiota upregulates EI24 in AMs to favor their homeostasis, but it retards their immune surveillance function in the lung. Our study thus indicates that deleting EI24 enhances anti-viral and anti-tumor effects of macrophage-based immunotherapy. Regulation of alveolar macrophage function requires further investigation. The authors here show that EI24, elicited by commensal microbiota, decreases alveolar macrophage phagocytosis and inflammatory responses against lung infection and tumor metastasis, whereas targeting EI24 enhances anti-viral and anti-tumor effects of macrophages.

TGF-β-activated kinase 1 (TAK1) is a key signaling hub and drug target in inflammatory responses. Although metabolism has been critically linked to immune cell function and inflammation, the metabolic control of TAK1 activation and intervention strategy remains to be explored. Here, we show that SM934, a derivative of the traditional Chinese medicine artemisinin, inhibits inflammatory responses via targeting α-enolase and inhibiting metabolite phosphoenolpyruvate (PEP) production. PEP directly binds TAK1 and inhibits its ubiquitination at the lysine-72 site, which promotes NF-κB activation and inflammatory responses. Overall, our study demonstrates a metabolic control of TAK1 stabilization and proposes that it could be disrupted by the derivative of the natural product artemisinin.

Neuronal communication relies on neurotransmitter release from synaptic vesicles. The endocytic protein AP180 is critical for efficient vesicle recycling at presynaptic terminals, and its loss impairs neurotransmission, producing reduced release frequency, enlarged synaptic vesicles, and increased quantal amplitude. Yet how AP180 controls vesicle size and whether vesicle size influences release remains unclear. Here, we show that the C-terminal Assembly domain (AD) of AP180 determines vesicle size and thereby regulates release properties in Caenorhabditis elegans. An AP180 variant lacking the AD (AP180∆AD) increases release frequency, contrasting sharply with the reduced transmission in ap180 null mutants, yet fails to correct the vesicle size or quantal amplitude. These enlarged vesicles evade curvature-dependent inhibition by complexin, a presynaptic regulator of fusion, while remaining dependent on complexin for evoked responses. This selective escape reveals that vesicle size influences release dynamics through curvature-sensing proteins. Replacing the AP180 AD with actin-binding motifs restores normal vesicle size, quantal amplitude, and release frequency, indicating that actin interactions are both necessary and sufficient for AD function. Biochemically, we show that the intrinsically disordered AD forms condensates that enrich actin monomers and nucleate filament assembly, while full-length AP180 couples PIP2-rich membranes to actin filaments. Together, these findings reveal that the AP180 AD regulates synaptic vesicle size through actin binding, establishing vesicle morphology as a key influencer of curvature-dependent release control.

To investigate the association between insulin resistance (IR) and all-cause mortality among adults with rheumatoid arthritis (RA). In this cohort study, we included 1,427 adults with self-reported RA from the National Health and Nutrition Examination Survey (NHANES) 1999–2010 and 2015–2018. IR was assessed using the homeostatic model assessment of insulin resistance (HOMA-IR). Survey-weighted multivariable Cox proportional hazards models were used to evaluate the association between HOMA-IR and all-cause mortality. During a mean follow-up of 9.7 years, 491 deaths occurred. Compared with participants in the lowest tertile of HOMA-IR, the multivariable-adjusted hazard ratios (HRs) and 95

Glioblastoma (GBM) is a highly lethal brain tumor, with therapeutic efforts hampered by the restrictive blood-brain barrier (BBB) and a profoundly immunosuppressive tumor microenvironment (TME). Driven by bioinformatics analysis identifying epidermal growth factor receptor (EGFR) and caspase-3 as key regulators of an immune-evasive pyroptosis pathway, we screened natural compounds and identified quercetin (Q) and chlorogenic acid (C) as dual-targeting agents, thereby laying a therapeutic foundation for amplifying pyroptosis in GBM treatment. The compounds were conjugated into a glutathione-responsive prodrug (QSSC) and encapsulated in a tumor-derived exosome-liposome nanoplatform (QSSC@Exo-LNP), enabling enhanced BBB penetration and intracranial targeting. Mechanistic studies revealed a dual-pathway amplification of pyroptosis, in which C directly activates caspase-8 to initiate gasdermin E (GSDME)-mediated pyroptosis, while Q/C-mediated EGFR inhibition activates mitochondrial pro-apoptotic protein, thereby augmenting caspase-3 and intensifying pyroptotic cell death. Upon intravenous injection, QSSC@Exo-LNP triggers robust pyroptosis, releasing DAMPs and tumor antigens for immune activation and macrophage reprogramming, converting the TME from "cold" to "hot" state. Moreover, this treatment strategy can significantly inhibit the distant tumors in the primary-distal orthotopic GBM model. This study proposes a strategy for the precise immunotherapy of GBM by exploiting natural products to target overexpressed GSDME and induce the pyroptotic cascade.

Polymorphisms of mouse chitinase-like protein 3 (Chil3), a member of the mammalian chitinase-like protein (CLP) family, have been demonstrated to be associated with inflammatory diseases by regulating lipid metabolism. However, the specific immunomodulatory impacts of CLPs, mainly mouse CHIL3 and its human functional homologue chitinase-3-like 2 (CHI3L2), on macrophage cholesterol metabolism and atherosclerosis have remained unclear. Here, we find CLPs (CHIL3 and CHI3L2) accelerate atherogenesis in a macrophage-dependent manner. Mechanistically, we identify an autocrine mechanism through which CLPs regulate cholesterol metabolism in macrophages. Macrophage-secreted CLPs exacerbate lipid uptake by binding to CD36. CLPs exhibit glycosidase activity, targeting and hydrolyzing N-glycosylated glycans on CD36, predominantly at sites N220 and N321, thereby enhancing lipid uptake. Increased lipid influx activates mTOR in macrophages, driving their transition to a pro-inflammatory phenotype while simultaneously suppressing peroxisome proliferator-activated receptor gamma (PPARγ) expression and thus impairing ABCG1-mediated cholesterol efflux. Single-cell sequencing reveals that CLPs increase atherosclerotic foamy macrophages, favoring vascular smooth muscle cells (VSMC) transformation into foam and osteoblast-like cells. Additionally, neutralizing antibodies targeting CHI3L2 prevent and treat atherosclerosis. These findings highlight the potential of CLPs as targets for disease diagnosis and therapy.

Autoimmune diseases are a group of disorders with multiple etiologies that disrupt normal immunological function, leading to the immune system mistakenly attacking the body’s own tissues. The Notch signaling pathway is a conserved pathway that is in part responsible for multiple cellular behaviors, including proliferation, differentiation, development, and death, through direct cell-to-cell communication. The expression and activation of Notch signaling pathway proteins are aberrantly regulated in autoimmune diseases in a manner that is closely related to their onset and development. We reviewed the functioning of the Notch signaling pathway in several autoimmune disorders, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjögren’s syndrome (pSS), juvenile idiopathic arthritis (JIA), idiopathic thrombocytopenic purpura (ITP), multiple sclerosis (MS), autoimmune vasculitis, autoimmune hepatitis (AIH), autoimmune thyroid disease (AITD), autoimmune kidney diseases and type 1 diabetes mellitus (T1DM). We specifically sought to explore the involvement of the Notch signaling pathway in the occurrence and progression of RA to provide ideas and approaches for developing new therapeutic strategies for this autoimmune disease.

Acute kidney injury (AKI) is a major public health issue. Solute carrier family 38 member 6 (SLC38A6) is known to mediate Na+-dependent net uptake and efflux of small neutral amino acids, but the role it plays in AKI still needs to be explored. In this study, we generated mice with Slc38a6 genetically deleted in tubular epithelial cells by crossing Slc38a6fl/fl mice with KspCre mice, which are transgenic mice that express Cre recombinase exclusively in tubular epithelial cells in the kidney and developing genitourinary tract. The mice were intraperitoneally injected with cisplatin. Separately, SLC38A6 was knocked down in HK-2 cells using siRNA, followed by treatment with cisplatin. Blood urea nitrogen (BUN) and Serum Creatinine (SCr) levels were used to measure renal function, and PAS and H&E staining, along with detection of NGAL expression was used to assess kidney injury. Tunel staining and the expression of apoptosis-related proteins were used to detect kidney cell apoptosis. Transcriptome sequencing was performed to explore the mechanism underlying our phenotypic observations, and lipid deposition was determined using Oil Red O staining. The expression of key enzymes of the fatty acid β-oxidation (FAO) pathway was detected using Western blotting and RT-qPCR. After induction of AKI, Slc38a6fl/flKspCre mice exhibited improved renal function, alleviated kidney injury, and decreased tubular cell apoptosis. Similarly, knocking down SLC38A6 in HK-2 cells significantly abrogated apoptosis induced by AKI. Transcriptome sequencing data confirmed that several pathways involved in fatty acid metabolism were activated in Slc38a6fl/flKspCre mice. Both Slc38a6fl/flKspCre mice and SLC38A6-knocked down HK-2 cells exhibited decreased lipid deposition and increased expression of key enzymes of the FAO pathway. We therefore conclude that SLC38A6-deficiency alleviates cisplatin-induced AKI by decreasing cell apoptosis and promoting FAO.

BackgroundMicroglia are central mediators of neuroinflammation in Alzheimer's disease (AD), contributing significantly to disease pathogenesis. Understanding microglial heterogeneity and their regulatory mechanisms is critical for identifying potential therapeutic targets.ObjectiveThis study aimed to investigate the diversity of microglial subpopulations in AD and uncover key transcriptional regulators driving their pathogenic activity.MethodsWe integrated bulk RNA sequencing data from AD patients and 5×FAD mouse models with single-cell RNA sequencing (scRNA-seq) to profile microglial heterogeneity. Differential gene expression, pathway enrichment, pseudotime trajectory, and SCENIC analyses were used to identify functionally distinct subsets and regulatory networks. Experimental validation was conducted through in vivo assays in 5×FAD mice and in vitro inhibition studies targeting HIF-1α.ResultsA unique microglial subpopulation, termed microglia_2, was identified with an inflammatory-angiogenic transcriptional signature that was enriched during AD progression. This subset showed significant activation of inflammatory pathways. Pseudotime and SCENIC analyses revealed HIF-1α as a master regulator of microglia_2. In 5×FAD mice, cognitive decline was accompanied by increased expression of HIF-1α and Apoe, as well as microglial activation in the prefrontal cortex. In vitro inhibition of HIF-1α significantly reduced microglial inflammation.ConclusionsOur study demonstrates that a specific microglial subpopulation characterized by elevated HIF-1α expression may contribute to AD-associated neuroinflammation. By integrating transcriptomic analyses and experimental validation, we provide cell type-specific insights into disease mechanisms, offering potential insights for future mechanistic studies and therapeutic exploration.

This study investigated the relationship between hypoxia stress priming and resistance to Vibrio parahaemolyticus infection in ridgetail white prawns ( Exopalaemon carinicauda ). Females and males were compared between group H (hypoxia‐primed) and group C (control). Four groups—CF, HF, CM, and HM—were infected with an established LC50 dose (1.46 × 10 5 CFU/mL) of V. parahaemolyticus . After 96 h, the survival rate of the hypoxia‐primed groups (HF and HM) exceeded 50%, which was significantly higher than the control groups (CF and CM) (less than 40% survival). Bacterial load analysis revealed significantly higher ( p < 0.01) mean V. parahaemolyticus loads at 96 h in the control groups (CF: 3.97 × 10 5 CFU/mg; CM: 2.71 × 10 5 CFU/mg) compared to the hypoxia‐primed groups (HF: 2.60 × 10 5 CFU/mg; HM: 1.22 × 10 5 CFU/mg), with significant differences persisting at 120 h. The analysis confirmed a significant positive correlation between hypoxia stress priming and resistance to infection, evidenced by a significant negative correlation between hypoxia stress priming and bacterial load in both males ( r = −0.574, p < 0.01) and females ( r = −0.496, p < 0.01). In other words, the hypoxia stress priming corresponded to a lower bacterial load (higher resistance). Transcriptome analysis of hepatopancreatic tissues identified 106 differentially expressed genes (39 up, 67 down) in hypoxia‐primed versus control prawns. The genes were primarily enriched in metabolic pathways (KEGG: beta‐alanine metabolism, metabolic pathways, glycolysis/gluconeogenesis, carbon metabolism, propanoate metabolism) related to functions in cell wall components and carbohydrate/GABA processes (GO: hyphal/fungal‐type cell wall, carbohydrate metabolic process, gamma‐aminobutyric acid catabolic/metabolic processes). The different expression levels of these genes may explain the variation in resistance to V. parahaemolyticus infection linked to hypoxia stress priming.

Necrotizing enterocolitis (NEC) is a serious inflammatory gastrointestinal disorder leading to a devastating intestinal inflammatory response, which typically results in severe sepsis and death. Given the imbalance of inflammatory response in the intestine that results in immune dysregulation and further worsens the clinical symptoms of NEC. Macrophages are the primary cells responsible for the early regulation and resolution of intestinal inflammation, therefore our experiments focus on the regulation of the polarization type of macrophages. In this study, we applied a convenient and continuous extrusion system to execute and purify M2NVs from RAW264.7 macrophage cells, then used to interfere with the LPS-induced cell inflammation model and NEC animal model. We discovered that M2NVs could foster the polarization of M1 to M2 macrophages and inhibit inflammatory injury in vivo, aligning with the in vitro results. Meanwhile, our study also revealed that M2NVs intervention could not only effectively alleviate the intestinal inflammatory environment, but also affect the changes in intestinal metabolism via omics techniques. Overall, the engineering strategy of M2NVs represents a promising approach with great potential for NEC treatment.

BACKGROUND:LIM domain-containing protein 2 (LIMD2) is known to promote metastasis in several cancers. However, its role and underlying mechanisms in colon cancer remain unclear. This study focused on investigating the prognostic value, functional impact, and molecular mechanisms of LIMD2 in colon cancer. METHODS:LIMD2 expression in colon cancer tissues and matched non-cancerous tissues was detected using RT-qPCR and immunohistochemistry. The chi-square test was used to assess the association between LIMD2 expression and clinicopathological characteristics. Kaplan-Meier survival analysis and Cox proportional hazards models were applied to evaluate the prognostic value of LIMD2. The functional role of LIMD2 in colon cancer cell migration was examined through Transwell and wound healing assays. Additionally, RNA sequencing (RNA-seq), co-immunoprecipitation (CoIP), silver staining, and mass spectrometry were performed to uncover the role of LIMD2 in colon cancer cell migration. RESULTS:LIMD2 expression was significantly increased in colon cancer samples and cell lines. High LIMD2 expression was positively correlated with lymph node metastasis and TNM stage. Patients with elevated LIMD2 expression exhibited poorer overall survival (OS). Gain-of-function assays demonstrated that LIMD2 accelerated colon cancer cell migration. RNA-seq analysis revealed that LIMD2 regulates ECM-receptor interactions and focal adhesion pathways. Furthermore, CoIP and mass spectrometry identified cofilin1 as a LIMD2-interacting protein. CONCLUSIONS:Our findings indicate that LIMD2 serves as a novel prognostic biomarker and potential target for colon cancer treatment.

Pneumonia frequently causes mass mortality in raccoon dogs, resulting in significant economic loss. Additionally, raccoon dogs carry various zoonotic pathogens. This study systematically assessed pulmonary pathogens in raccoon dogs and their potential public health implications utilizing 2bRAD microbiome sequencing (2bRAD-M) and viral metagenomics. We analyzed 30 lung tissue samples for microbial composition. Sequencing revealed Pseudomonadota, Ascomycota, and Actinobacteria as dominant phyla and Acinetobacter, Escherichia, and Klebsiella as predominant genera. The most abundant species were Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae. In total, 158 species across 84 genera were identified, including 49 potentially zoonotic species. Viral metagenomics revealed Peduoviridae, Rountreeviridae, and Parvoviridae as dominant families, with Valbvirus ValB1MD2, Andhravirus andhra, and Amdoparvovirus carnivoran3 comprising over 80% of the viral composition. These findings highlight the pathogenic complexity of raccoon dog pneumonia and its zoonotic risks, providing crucial insights for disease control and public health management.

Circular RNAs play crucial roles in tumor progression and drug resistance. We previously reported that circSETD3 is downregulated in colorectal cancer (CRC) and correlates with tumor size and metastasis; however, the precise biological functions and underlying the mechanisms of action of circSETD3 in CRC remain unclear. Therefore, in the present study, we aimed to investigate the role of circSETD3 in CRC growth, metastasis, and cetuximab resistance using in vitro and in vivo functional assays. Our results demonstrated that circSETD3 acts as a tumor suppressor in CRC progression and cetuximab resistance. Mechanistically, RNA-seq, FISH, dual-luciferase reporter assays, and ChIP assays revealed that reduced circSETD3 expression in CRC activated ErbB3 and its downstream Akt pathway. Notably, we found that the Akt pathway upregulated ErbB3 transcription via HIF1A, indicating the presence of a novel positive feedback loop between ErbB3 and Akt pathway which reinforces CRC progression and drives cetuximab resistance. Furthermore, circSETD3 deficiency in CRC triggered a feedback loop through the miR-4667-5p-RASA4 axis which was effectively suppressed by exosomal circSETD3 supplementation. Thus, our findings highlight circSETD3 to be a promising therapeutic target for inhibiting CRC progression and overcoming cetuximab resistance.

Accurately predicting the temporal and spatial distribution of intraocular drugs to enhance anti-glaucoma treatment efficacy remains a significant challenge in clinical ophthalmology. Developing more precise numerical models of intraocular drug transport holds substantial clinical value. This study establishes a model of intraocular drug transport, which includes the trabecular meshwork (TM), collector channels (CC), and uveoscleral outflow pathway, and analyzes the parameters affecting aqueous humor (AH) outflow and the impact of the uveoscleral pathway on drug transport. Results indicate that the uveoscleral pathway influences AH outflow, with its porous media significantly impeding drug clearance, leading to drug accumulation in the anterior chamber and higher concentrations in the TM. A reduction in TM porosity or the number of CC hinders drug transport to varying extents, increasing peak drug concentration at TM targets by 11.27% and 12.8%, respectively. Furthermore, neglecting the uveoscleral pathway may result in an 10.93% underestimation of TM drug concentration. This study provides insight into the pathways involved in anti-glaucoma drug transport, contributing to the optimization of drug design for improved therapeutic outcomes.

Dysfunction of invariant natural killer T (iNKT) cells contributes to immune resistance of tumors. Most mechanistic studies focus on their static functional status before or after activation, not considering motility as an important characteristic for antigen scanning and thus anti-tumor capability. Here we show via intravital imaging, that impaired motility of iNKT cells and their exclusion from tumors both contribute to the diminished anti-tumor iNKT cell response. Mechanistically, CD1d, expressed on macrophages, interferes with tumor infiltration of iNKT cells and iNKT-DC interactions but does not influence their intratumoral motility. VCAM1, expressed by cancer cells, restricts iNKT cell motility and inhibits their antigen scanning and activation by DCs via reducing CDC42 expression. Blocking VCAM1-CD49d signaling improves motility and activation of intratumoral iNKT cells, and consequently augments their anti-tumor function. Interference with macrophage-iNKT cell interactions further enhances the anti-tumor capability of iNKT cells. Thus, our findings provide a direction to enhance the efficacy of iNKT cell-based immunotherapy via motility regulation.

Neurons are highly polarized cells with dendrites and axons. Dendrites, which receive sensory information or input from other neurons, often display elaborately branched morphologies. While mechanisms that promote dendrite branching have been widely studied, less is known about the mechanisms that restrict branching. Using the nematode Caenorhabditis elegans, we identify rabr-1 (for Rab-related gene 1) as a factor that restricts branching of the elaborately branched dendritic trees of PVD and FLP somatosensory neurons. Animals mutant for rabr-1 show excessively branched dendrites throughout development and into adulthood in areas where the dendrites overlay epidermal tissues. Phylogenetic analyses show that RABR-1 displays similarity to small GTPases of the Rab-type, although based on sequence alone, no clear vertebrate ortholog of RABR-1 can be identified. We find that rabr-1 is expressed and can function in epidermal tissues, suggesting that rabr-1 restricts dendritic branching cell-nonautonomously. Genetic experiments further indicate that for the formation of ectopic branches rabr-1 mutants require the genes of the Menorin pathway, which have been previously shown to mediate dendrite morphogenesis of somatosensory neurons. A translational reporter for RABR-1 reveals a subcellular localization to punctate, perinuclear structures, which correlates with endosomal and autophagosomal markers, but anticorrelates with lysosomal markers suggesting an amphisomal character. Point mutations in rabr-1 analogous to key residues of small GTPases suggest that rabr-1 functions in a GTP-bound form independently of GTPase activity. Taken together, rabr-1 encodes for an atypical small GTPase of the Rab-type that cell-nonautonomously restricts dendritic branching of somatosensory neurons, likely independently of GTPase activity.