Biology subjects

Abrisch, R. G.

Publications and source records attributed to Abrisch, R. G..

5 recordsLinked to original sources

bioRxiv2026

The molecular architecture of tunneling nanotubes

Tunneling nanotubes (TNTs) are thin intercellular bridges that mediate the exchange of proteins, organelles, and nucleic acids between neighboring cells. They are enriched in tumor cells, implicated in chemotherapy resistance, induced in models of aggregation-based diseases, and their formation is stimulated by viruses that use TNTs to enhance infection. Despite their broad relevance and therapeutic potential, TNT morphology and function remain poorly understood, owing to the absence of clear morphological criteria and the limitations of light microscopy. Here, we establish two complementary systems to study TNT formation and function: stimulation with the pseudorabies viral kinase US3 to model viral transmission, and treatment of acute monocytic leukemia THP-1 cells with daunorubicin to model chemotherapy resistance. Using live-cell imaging, we characterize cytoskeletal organization and bidirectional lysosome transport in both contexts, and apply cryo-correlative light and electron microscopy (cryo-CLEM) with cryogenic electron tomography (cryo-ET) to visualize TNTs in their native state at molecular resolution. We show that TNTs display a rich molecular architecture, comprising actin filaments, microtubules, intermediate filaments, active ribosomes, and diverse organelles including multivesicular bodies, autophagosomes, and lysosomes. Sub-nanometer microtubule reconstructions reveal mixed polarity within individual TNTs, suggesting that both connected cells actively contribute to TNT formation and cargo trafficking. This organization is conserved across both systems, implying that TNT biogenesis reflects a shared cellular program rather than a context-specific response. Our findings provide the first structural framework for TNTs, revealing an unexpectedly rich molecular architecture and laying the groundwork for understanding how TNTs orchestrate intercellular communication in disease.

cell biology↗

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↗

bioRxiv2022

Structure of LRRK1 and mechanisms of autoinhibition and activation

Leucine Rich Repeat Kinase 1 and 2 (LRRK1 and LRRK2) are homologs in the ROCO family of proteins in humans. Despite their shared domain architecture and involvement in intracellular trafficking, their disease associations are strikingly different: LRRK2 is involved in familial Parkinsons Disease (PD) while LRRK1 is linked to bone diseases. Furthermore, PD-linked mutations in LRRK2 are typically autosomal dominant gain-of-function while those in LRRK1 are autosomal recessive loss-of-function. To understand these differences, we solved cryo-EM structures of LRRK1 in its monomeric and dimeric forms. Both differ from the corresponding LRRK2 structures. Unlike LRRK2, which is sterically autoinhibited as a monomer, LRRK1 is sterically autoinhibited in a dimer-dependent manner. LRRK1 has an additional level of autoinhibition that prevents activation of the kinase and is absent in LRRK2. Finally, we place the structural signatures of LRRK1 and LRRK2 in the context of the evolution of the LRRK family of proteins.

biochemistry↗