About

Barth Grant is a Distinguished Professor in the Department of Molecular Biology and Biochemistry at Rutgers University. His research focuses on the molecular mechanisms controlling membrane traffic, specifically endocytosis and endocytic recycling, which are essential for cellular function and have broad relevance to biomedicine. His work investigates how large molecules are internalized by cells and how the composition of cellular membranes is regulated to facilitate interactions with the environment. Grant's research utilizes the model organism Caenorhabditis elegans, taking advantage of its advanced genetics, including gene knockdown, knockout, and transgenic technology, as well as its transparent body that allows visualization of fluorescently tagged molecules in living animals. His studies emphasize trafficking mechanisms in the worm intestine, a simple polarized epithelium that maintains distinct plasma membrane domains. His work aims to understand how membrane-bound cargo is sorted in secretory and endocytic recycling pathways to maintain cellular polarity, with implications for understanding processes such as insulin-stimulated glucose transporter movement, cytokinesis, cell migration, and signal transduction. This research provides insights into fundamental cell biology and has potential applications in understanding diseases like type II diabetes and cancer.

Research topics

• Biology
• Cell biology
• Biochemistry
• Genetics
• Chemistry

Selected publications

• MassIVE MSV000101769 - SCM-1/SCAMP Maintains Microdomain Boundaries and Cargo Sorting within the Endosomal System

  UC San Diego · 2026-01-01

  datasetOpen access1st authorCorresponding
  PublisherDOI

• PIKI-1, a class II PI 3-kinase, functions in endocytic trafficking

  PLoS Genetics · 2026-02-13

  articleOpen access

  Cellular membrane trafficking, including endocytosis and exocytosis, is a complex process coordinated by trafficking-associated proteins, cargo molecules, the cytoskeleton, and membrane lipids. The NIMA-related kinases NEKL-2 (human NEK8/9) and NEKL-3 (human NEK6/7) are conserved regulators of membrane trafficking in Caenorhabditis elegans that are required for the completion of molting. Using a genetic approach, we isolated reduction-of-function mutations in piki-1 that suppress nekl-associated molting defects. piki-1 encodes the sole predicted C. elegans Class II PI 3-kinase (PI3K), a relatively understudied class of lipid modifiers that contribute to the production of PI 3-phosphate (PI(3)P) and PI 3,4-bisphosphate (PI(3,4)P2). Using genetically encoded lipid sensors, we found that PIKI-1 was responsible for the production of PI(3,4)P2 in the C. elegans epidermis but played only a minor role in contributing to PI(3)P levels. Consistent with this, both PI(3,4)P2 and PIKI-1 partially colocalized to early endosomes, and reduction of PIKI-1 affected the size and protein composition of early endosomal compartments marked by RAB-5, EEA-1, and SNX-1. Reduced PIKI-1 also led to increased tubulation of endosomal compartments associated with recycling or the degradation of cellular debris. In contrast to studies using mammalian cell culture, PIKI-1 was largely dispensable for clathrin-mediated endocytosis in the worm epidermis, a polarized epithelium. Notably, reduction of PIKI-1 function mitigated defects in early endosomes associated with the depletion of NEKL-2. We propose that reduction of PIKI-1 function may suppress nekl molting defects by partially restoring endocytic trafficking function within a subset of compartments, including the early endosome. We also show that inhibition of HIPR-1, an ortholog of the mammalian PI(3,4)P₂-binding proteins, HIP1 and HIPR1, suppresses nekl molting defects, consistent with a model that loss of PIKI-1 alters the binding of endocytic regulators in a manner that partially compensates for the loss of NEKL-2 activity.

  PublisherDOI

• SCM-1/SCAMP Maintains Microdomain Boundaries and Cargo Sorting within the Endosomal System

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-05-21

  articleSenior authorCorresponding

  After endocytosis, transmembrane cargo reaches sorting endosomes where it is partitioned into physically distinct recycling or degradative microdomains. While the J-domain protein RME-8/DNAJC13 is known to maintain these boundaries by actively removing degradative machinery from the recycling microdomain, other factors that contribute to this spatial organization remain poorly defined. Here, we identify the conserved tetraspan protein SCM-1/SCAMP as a key microdomain organizer, discovered through RME-8 proximity-dependent biotinylation screens in C. elegans and human cells. Leveraging the large endosomes of C. elegans coelomocytes, we show that SCM-1 is selectively enriched within the recycling microdomain. In scm-1 mutants, recycling and degradative microdomains still assemble but fail to remain spatially distinct, resulting in inappropriate microdomain overlap. This loss of boundary integrity occurs without increasing the recruitment of sorting machineries, indicating a mechanism distinct from the RME-8-mediated uncoating pathway. scm-1 mutants exhibit significant sorting defects, including misrouting of recycling cargo MIG-14/Wls and v-SNARE SNB-2/VAMP3 to late endosomes and lysosomes. We find that snb-2 mutants themselves missort MIG-14 to late endosomes and lysosomes, suggesting that SNB-2 sorting is key for recycling function. Our data suggest that both microdomains lose efficiency in scm-1 mutants, as cargo missorted into late endosomes and lysosomes is not depleted overall, and degradation of an independent ESCRT-dependent cargo is delayed. We conclude that SCM-1 ensures endosomal sorting fidelity by stabilizing microdomain boundary integrity, a process required for efficient recycling and degradation of transmembrane cargo.

  PublisherDOI

• PIKI-1, a class II phosphatidylinositol 3-kinase, functions in endocytic trafficking

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-23 · 2 citations

  preprintOpen access

  Abstract Membrane trafficking, including endocytosis and exocytosis, is a complex process that is coordinated by trafficking-associated proteins, cargo molecules, the cytoskeleton, and membrane lipid composition. The NIMA-related kinases NEKL-2 (human NEK8/9) and NEKL-3 (human NEK6/7) are conserved regulators of membrane trafficking in Caenorhabditis elegans and are required for successful molting. Through a genetic approach, we isolated reduction-of-function mutations in piki-1 that suppress nekl- associated molting defects. piki-1 encodes the sole predicted C. elegans Class II phosphatidylinositol 3-kinase (PI3Ks), an understudied class of lipid modifiers that contribute to the production of phosphatidylinositol 3-phosphate (PI(3)P) and phosphatidylinositol 3,4-bisphosphate (PI(3,4)P 2 ). Using a set of genetically encoded lipid sensors, we found that PIKI-1 was responsible for the production of PI(3,4)P 2 in the C. elegans epidermis but played only a minor role in the control of PI(3)P levels. Consistent with this, both PI(3,4)P 2 and PIKI-1 colocalized to early endosomes, and reduction of PIKI-1 function strongly affected early endosomal morphology and protein composition. Additionally, reduced PIKI-1 function led to excess tubulation of endosomal compartments associated with recycling or the degradation of cellular debris. In contrast to previous studies using mammalian cell culture, PIKI-1 was largely dispensable for clathrin-mediated endocytosis in the context of the worm epidermis, which is a polarized epithelium. Notably, reduction of PIKI-1 function strongly mitigated defects in early endosomes associated with the depletion of NEKL-2. We propose that reduction of PIKI-1 function may suppress nekl molting defects by partially restoring endocytic trafficking within specific compartments, including the early endosome. We also show that inhibition of the PI(3,4)P 2 -binding protein HIPR-1 (HIP1/HIPR1) suppresses nekl molting defects, suggesting that reduced PI(3,4)P 2 levels alter endosomal protein recruitment in a manner that antagonizes NEKL-2 function. Author summary The uptake of materials from outside the cell and their subsequent delivery to specific intracellular locations are essential for cell function and survival. Two of the mechanisms that control this complex intracellular pathway involve the modification of proteins and of lipids, processes that are highly conserved across species. In this study, we used the model organism Caenorhabditis elegans , which is highly amenable to cell biological and genetic approaches, to establish a novel connection between these two regulatory mechanisms and demonstrate the importance of lipid modifications in maintaining the normal functioning of intracellular transport. Our results also provide insights into the fundamental cellular functions of proteins associated with human disease including cancer and metabolic disease.

  PublisherOA PDFDOI

• Author response: Mechanical force of uterine occupation enables large vesicle extrusion from proteostressed maternal neurons

  2024-07-31

  peer-reviewOpen access

  Large vesicle extrusion from neurons may contribute to spreading pathogenic protein aggregates and promoting inflammatory responses, two mechanisms leading to neurodegenerative disease. Factors that regulate extrusion of large vesicles, such as exophers produced by proteostressed C. elegans touch neurons, are poorly understood. Here we document that mechanical force can significantly potentiate exopher extrusion from proteostressed neurons. Exopher production from the C. elegans ALMR neuron peaks at adult day 2 or 3, coinciding with the C. elegans reproductive peak. Genetic disruption of C. elegans germline, sperm, oocytes, or egg/early embryo production can strongly suppress exopher extrusion from the ALMR neurons during the peak period. Conversely, restoring egg production at the late reproductive phase through mating with males or inducing egg retention via genetic interventions that block egg-laying can strongly increase ALMR exopher production. Overall, genetic interventions that promote ALMR exopher production are associated with expanded uterus lengths and genetic interventions that suppress ALMR exopher production are associated with shorter uterus lengths. In addition to the impact of fertilized eggs, ALMR exopher production can be enhanced by filling the uterus with oocytes, dead eggs, or even fluid, supporting that distention consequences, rather than the presence of fertilized eggs, constitute the exopher-inducing stimulus. We conclude that the mechanical force of uterine occupation potentiates exopher extrusion from proximal proteostressed maternal neurons. Our observations draw attention to the potential importance of mechanical signaling in extracellular vesicle production and in aggregate spreading mechanisms, making a case for enhanced attention to mechanobiology in neurodegenerative disease.

  PublisherDOI

• Reviewer #1 (Public Review): Mechanical force of uterine occupation enables large vesicle extrusion from proteostressed maternal neurons

  2024-02-19

  peer-reviewOpen access

  Large vesicle extrusion from neurons may contribute to spreading pathogenic protein aggregates and promoting inflammatory responses, two mechanisms leading to neurodegenerative disease. Factors that regulate extrusion of large vesicles, such as exophers produced by proteostressed C. elegans touch neurons, are poorly understood. Here we document that mechanical force can significantly potentiate exopher extrusion from proteostressed neurons. Exopher production from the C. elegans ALMR neuron peaks at adult day 2 or 3, coinciding with the C. elegans reproductive peak. Genetic disruption of C. elegans germline, sperm, oocytes, or egg/early embryo production can strongly suppress exopher extrusion from the ALMR neurons during the peak period. Conversely, restoring egg production at the late reproductive phase through mating with males or inducing egg retention via genetic interventions that block egg-laying can strongly increase ALMR exopher production. Overall, genetic interventions that promote ALMR exopher production are associated with expanded uterus lengths and genetic interventions that suppress ALMR exopher production are associated with shorter uterus lengths. In addition to the impact of fertilized eggs, ALMR exopher production can be enhanced by filling the uterus with oocytes, dead eggs, or even fluid, supporting that distention consequences, rather than the presence of fertilized eggs, constitute the exopher-inducing stimulus. We conclude that the mechanical force of uterine occupation potentiates exopher extrusion from proximal proteostressed maternal neurons. Our observations draw attention to the potential importance of mechanical signaling in extracellular vesicle production and in aggregate spreading mechanisms, making a case for enhanced attention to mechanobiology in neurodegenerative disease.

  PublisherDOI

• Mechanical force of uterine occupation enables large vesicle extrusion from proteostressed maternal neurons

  2024-02-19 · 2 citations

  preprintOpen access

  Abstract Large vesicle extrusion from neurons may contribute to spreading pathogenic protein aggregates and promoting inflammatory responses, two mechanisms leading to neurodegenerative disease. Factors that regulate extrusion of large vesicles, such as exophers produced by proteostressed C. elegans touch neurons, are poorly understood. Here we document that mechanical force can significantly potentiate exopher extrusion from proteostressed neurons. Exopher production from the C. elegans ALMR neuron peaks at adult day 2 or 3, coinciding with the C. elegans reproductive peak. Genetic disruption of C. elegans germline, sperm, oocytes, or egg/early embryo production can strongly suppress exopher extrusion from the ALMR neurons during the peak period. Conversely, restoring egg production at the late reproductive phase through mating with males or inducing egg retention via genetic interventions that block egg-laying can strongly increase ALMR exopher production. Overall, genetic interventions that promote ALMR exopher production are associated with expanded uterus lengths and genetic interventions that suppress ALMR exopher production are associated with shorter uterus lengths. In addition to the impact of fertilized eggs, ALMR exopher production can be enhanced by filling the uterus with oocytes, dead eggs, or even fluid, supporting that distention consequences, rather than the presence of fertilized eggs, constitute the exopher-inducing stimulus. We conclude that the mechanical force of uterine occupation potentiates exopher extrusion from proximal proteostressed maternal neurons. Our observations draw attention to the potential importance of mechanical signaling in extracellular vesicle production and in aggregate spreading mechanisms, making a case for enhanced attention to mechanobiology in neurodegenerative disease.

  PublisherOA PDFDOI

• LRK-1/LRRK2 and AP-3 regulate trafficking of synaptic vesicle precursors through active zone protein SYD-2/Liprin-α

  PLoS Genetics · 2024-05-09 · 9 citations

  articleOpen accessCorresponding

  Synaptic vesicle proteins (SVps) are transported by the motor UNC-104/KIF1A. We show that SVps travel in heterogeneous carriers in C. elegans neuronal processes, with some SVp carriers co-transporting lysosomal proteins (SV-lysosomes). LRK-1/LRRK2 and the clathrin adaptor protein complex AP-3 play a critical role in the sorting of SVps and lysosomal proteins away from each other at the SV-lysosomal intermediate trafficking compartment. Both SVp carriers lacking lysosomal proteins and SV-lysosomes are dependent on the motor UNC-104/KIF1A for their transport. In lrk-1 mutants, both SVp carriers and SV-lysosomes can travel in axons in the absence of UNC-104, suggesting that LRK-1 plays an important role to enable UNC-104 dependent transport of synaptic vesicle proteins. Additionally, LRK-1 acts upstream of the AP-3 complex and regulates its membrane localization. In the absence of the AP-3 complex, the SV-lysosomes become more dependent on the UNC-104-SYD-2/Liprin-α complex for their transport. Therefore, SYD-2 acts to link upstream trafficking events with the transport of SVps likely through its interaction with the motor UNC-104. We further show that the mistrafficking of SVps into the dendrite in lrk-1 and apb-3 mutants depends on SYD-2, likely by regulating the recruitment of the AP-1/UNC-101. SYD-2 acts in concert with AP complexes to ensure polarized trafficking & transport of SVps.

  PublisherOA PDFDOI

• Reviewer #3 (Public Review): Mechanical force of uterine occupation enables large vesicle extrusion from proteostressed maternal neurons

  2024-02-19

  peer-reviewOpen access

  Large vesicle extrusion from neurons may contribute to spreading pathogenic protein aggregates and promoting inflammatory responses, two mechanisms leading to neurodegenerative disease. Factors that regulate extrusion of large vesicles, such as exophers produced by proteostressed C. elegans touch neurons, are poorly understood. Here we document that mechanical force can significantly potentiate exopher extrusion from proteostressed neurons. Exopher production from the C. elegans ALMR neuron peaks at adult day 2 or 3, coinciding with the C. elegans reproductive peak. Genetic disruption of C. elegans germline, sperm, oocytes, or egg/early embryo production can strongly suppress exopher extrusion from the ALMR neurons during the peak period. Conversely, restoring egg production at the late reproductive phase through mating with males or inducing egg retention via genetic interventions that block egg-laying can strongly increase ALMR exopher production. Overall, genetic interventions that promote ALMR exopher production are associated with expanded uterus lengths and genetic interventions that suppress ALMR exopher production are associated with shorter uterus lengths. In addition to the impact of fertilized eggs, ALMR exopher production can be enhanced by filling the uterus with oocytes, dead eggs, or even fluid, supporting that distention consequences, rather than the presence of fertilized eggs, constitute the exopher-inducing stimulus. We conclude that the mechanical force of uterine occupation potentiates exopher extrusion from proximal proteostressed maternal neurons. Our observations draw attention to the potential importance of mechanical signaling in extracellular vesicle production and in aggregate spreading mechanisms, making a case for enhanced attention to mechanobiology in neurodegenerative disease.

  PublisherDOI

• Mechanical force of uterine occupation enables large vesicle extrusion from proteostressed maternal neurons

  eLife · 2024-02-19 · 4 citations

  articleOpen access

  Large vesicle extrusion from neurons may contribute to spreading pathogenic protein aggregates and promoting inflammatory responses, two mechanisms leading to neurodegenerative disease. Factors that regulate the extrusion of large vesicles, such as exophers produced by proteostressed C. elegans touch neurons, are poorly understood. Here, we document that mechanical force can significantly potentiate exopher extrusion from proteostressed neurons. Exopher production from the C. elegans ALMR neuron peaks at adult day 2 or 3, coinciding with the C. elegans reproductive peak. Genetic disruption of C. elegans germline, sperm, oocytes, or egg/early embryo production can strongly suppress exopher extrusion from the ALMR neurons during the peak period. Conversely, restoring egg production at the late reproductive phase through mating with males or inducing egg retention via genetic interventions that block egg-laying can strongly increase ALMR exopher production. Overall, genetic interventions that promote ALMR exopher production are associated with expanded uterus lengths and genetic interventions that suppress ALMR exopher production are associated with shorter uterus lengths. In addition to the impact of fertilized eggs, ALMR exopher production can be enhanced by filling the uterus with oocytes, dead eggs, or even fluid, supporting that distention consequences, rather than the presence of fertilized eggs, constitute the exopher-inducing stimulus. We conclude that the mechanical force of uterine occupation potentiates exopher extrusion from proximal proteostressed maternal neurons. Our observations draw attention to the potential importance of mechanical signaling in extracellular vesicle production and in aggregate spreading mechanisms, making a case for enhanced attention to mechanobiology in neurodegenerative disease.

  PublisherDOI

Recent grants

• NIH Grant Z01AA000449

  NIH · $4.3M

• Understanding the Exopher: A Novel Mechanism for Extrusion of Neurotoxic Contents

  NIH · $4.2M · 2013–2023

• Molecular regulation of endosome fission during endocytic recycling

  NIH · $2.2M · 2020–2028

• NIH Grant R01GM103995

  NIH · $1.2M · 2018

• NIH Grant R21DK082854

  NIH · $401k · 2011

Frequent coauthors

• Madhura Castelino

  478 shared

• Meghna Jani

  University of Manchester

  390 shared

• James Bluett

  Versus Arthritis

  328 shared

• Anne Barton

  University of Manchester

  319 shared

• E G Chelliah

  Centre for Epidemiology Versus Arthritis

  294 shared

• Gillian Smith

  UK Health Security Agency

  294 shared

• G. Fragoulis

  Laiko General Hospital of Athens

  294 shared

• Hector Chinoy

  Manchester University NHS Foundation Trust

  268 shared

Education

• Ph.D., Molecular Biology

  Princeton University

  1996

• B.A., Biology

  University of Virginia

  1989