Biology subjects

Voeltz, G. K.

Publications and source records attributed to Voeltz, G. K..

5 recordsLinked to original sources

bioRxiv2026

ER-associated control of axonal vesicle trafficking during neuronal development

Axonal vesicle trafficking is essential for presynaptic assembly, yet the intracellular structures that spatially and temporally regulate vesicle transport during neuronal development remain unclear. Here we identify previously uncharacterized membrane contact sites (MCSs) between the endoplasmic reticulum (ER) and both synaptic vesicle precursors (SVPs) and dense-core vesicles (DCVs). Using super-resolution and cryo-electron microscopy, we reveal that vesicle transport undergoes a transient developmental slowdown in the axons of rat hippocampal neurons associated with increased vesicle tethering to the ER. Using proximity biotinylation, we identify the ER protein PRG1 as a developmentally regulated factor enriched at these sites that modulates vesicle mobility. Notably, a disease-associated PRG1 mutant fails to regulate vesicle trafficking. Finally, we demonstrate that PRG1 modulation of vesicle trafficking serves as a developmental checkpoint by delaying synapse formation and preventing premature network activity. Together, our findings establish ER-vesicle contact sites as a previously unrecognized layer of control of axonal trafficking and link intracellular organization to the timing of synapse assembly.

cell biology↗

bioRxiv2025

β-Coronavirus Nsp6 hijacks host ER translocation machineries into viral replication centers

{beta}-coronaviruses evade host immune detection by replicating their genomes within double membrane vesicles (DMVs) derived from endoplasmic reticulum (ER) membranes. For example, SARS-CoV and CoV-2 encode three non-structural membrane proteins (Nsp 3, 4, and 6) which can remodel the ER to form DMVs. Here we test whether Nsps also function to recruit key host machineries required for viral replication and assembly within ER-derived DMVs. We use mouse hepatitis virus to study whether {beta}-coronavirus Nsps coordinate ER remodeling with host machinery recruitment. We demonstrate that Nsp6 generates Nsp6-remodeled ER domains that sequester host ER insertases including the Sec61 translocon, EMC, and GEL complexes. FRAP and FLIP experiments confirm that Nsp6 domains remain continuous with the ER and do not restrict membrane protein diffusion, except for those insertases that are sequestered there by Nsp6. Together, these data demonstrate a dual role for Nsp6 in remodeling ER membranes and sequestering host translocation machinery away from the general ER and into DMVs.

molecular biology↗

bioRxiv2025

Nuclear envelope budding is a non-canonical mechanism to export large transcripts in muscle cells

In recent years, nuclear envelope budding (NEB) has emerged as an alternative route for nuclear export of viral particles that are too large to pass through the nuclear pore complex. Yet, the significance of this unconventional export pathway for large endogenous cargoes in mammalian cells has remained largely unexplored. Here, we use a combination of electron and fluorescence microscopy to demonstrate that NEB events occur following myoblast differentiation into myotubes and concomitant with the expression of extremely long muscle-specific transcripts. We show that NE buds are derived from the inner nuclear membrane, contain internal vesicles, and are specifically enriched with long sarcomeric transcripts. We identify a role for the protein UIF in regulating mRNA cargo targeting into NE buds and show that this pathway requires the ESCRT-III membrane remodeling machinery. Our findings uncover a non-canonical pathway for large transcript nuclear export in muscle cells and provide insight into its mechanism.

cell biology↗

bioRxiv2023

A Flat Protein Complex Shapes Rough ER Membrane Sheets

Rough ER sheets are a fundamental domain of the ER and the gateway into the secretory pathway. While reticulon proteins stabilize high-curvature ER tubules, it is unclear if other proteins scaffold the flat membranes of rough ER sheets. Through a proteomics screen using ER sheet localized RNA-binding proteins as bait, we identify the Sigma-1 receptor (SigmaR1) as an ER sheet shaping factor. High-resolution live cell imaging and electron tomography assign SigmaR1 as an ER sheet-localized factor whose levels determine the amount of rough ER sheets in cells. Structure-guided mutagenesis and in vitro reconstitution on giant unilamellar vesicles further support a mechanism whereby SigmaR1 oligomers use their extended arrays of amphipathic helices to bind and flatten the lumenal leaflet of ER membranes. Our results demonstrate an unexpected way for proteins to sense and propagate flat membrane sheets.

cell biology↗

bioRxiv2022

An ER phospholipid hydrolase drives ER-associated mitochondrial constriction for fission and fusion

Mitochondria are dynamic organelles that undergo cycles of fission and fusion at a unified platform defined by endoplasmic reticulum (ER)-mitochondria membrane contact sites (MCSs). These MCSs or nodes co-localize fission and fusion machinery. We set out to identify how ER-associated mitochondrial nodes can regulate both fission and fusion machinery assembly. We have used a promiscuous biotin ligase linked to the fusion machinery, Mfn1, and proteomics to identify an ER membrane protein, Aphyd, as a major regulator of node formation. In the absence of Aphyd, fission and fusion machineries fail to recruit to ER-associated mitochondrial nodes and fission and fusion rates are significantly reduced. Aphyd contains an acyltransferase motif and an /{beta} hydrolase domain and point mutations in critical residues of these regions fail to rescue the formation of ER-associated mitochondrial hot spots. These data suggest a mechanism whereby Aphyd functions by altering phospholipid composition at ER-mitochondria MCSs. Our data present the first example of an ER membrane protein that regulates the recruitment of both fission and fusion machineries to mitochondria.

cell biology↗