Biology subjects

Albacete-Albacete, L.

Publications and source records attributed to Albacete-Albacete, L..

4 recordsLinked to original sources

bioRxiv2026

FXR proteins and BICD2 cooperate to promote dynein-mediated RNP transport and stress granule assembly

Intracellular trafficking of ribonucleoprotein particles (RNPs) is a widespread strategy for regulating gene expression, yet how this process is orchestrated in mammalian systems remains unclear. Here, we show that Bicaudal D2 (BICD2), a partner of the microtubule motor dynein, is complexed with RNA-binding proteins (RBPs) in human cells. We also reveal that two of these RBPs - the Fragile X-related proteins FXR1 and FXR2 - bind directly to BICD2 and recruit mRNAs to dynein. Surprisingly, given its conventional designation as a cargo adaptor, BICD2 is not needed for dynein to interact with FXR1 and FXR2. Using in vitro reconstitution, we demonstrate that BICD2 instead activates dynein motility in concert with the FXR proteins. These data support a model in which BICD2 is recruited to pre-existing RNP-motor complexes, where it is licensed by the FXR proteins to activate processive movement. We further provide evidence that FXR proteins, BICD2 and dynein cooperate to promote rapid formation of stress granules, large RNPs that form in the cytoplasm in response to cellular insults. Collectively, our work reveals molecular mechanisms underlying RNP transport and stress granule assembly in human cells and indicates that cargo recruitment and motor activation are separable steps in dynein-mediated transport.

cell biology↗

bioRxiv2026

Dynein-dependent positioning of multiple organelles regulates adaptive gene expression during oxidative stress

Cells respond to environmental insults through well-characterized changes to their transcriptome and proteome. The contribution that reorganization of intracellular architecture makes to the adaptive stress response is much less understood. Here, we reveal a conserved spatial response to oxidative stress in which the microtubule motor dynein enhances perinuclear clustering of multiple membrane-bound organelles. These events are triggered by reactive oxygen species and protein kinase C and occur without increased association of dynein with its activator dynactin, pointing to a non-canonical mechanism for stimulating retrograde transport. Using a chemically-inducible system for dispersing individual organelles, we show that perinuclear localization of multiple compartments potentiates oxidative stress-induced gene expression, with distinct genes depending on inputs from either combinations of organelles or individual compartments. Together, these findings implicate positioning of multiple membrane-bound compartments in gene expression regulation and identify coordinated organelle trafficking by dynein as an additional regulatory layer in the cellular stress response.

cell biology↗

bioRxiv2024

Human tumor suppressor protein Pdcd4 binds at the mRNA entry channel in 40S small ribosomal subunit

Translation is regulated mainly in the initiation step, and its dysregulation is implicated in many human diseases. Several proteins have been found to regulate translational initiation, including Pdcd4 (programmed cell death gene 4). Pdcd4 is a tumor suppressor protein that prevents cell growth, invasion, and metastasis. It is downregulated in most tumor cells, while global translation in the cell is upregulated. To understand the mechanisms underlying translational control by Pdcd4, we used single-particle cryo-electron microscopy to determine the structure of human Pdcd4 bound to 40S small ribosomal subunit, including Pdcd4-40S and Pdcd4-40S-eIF4A-eIF3-eIF1 complexes. The structures reveal the binding site of Pdcd4 at the mRNA entry site in the 40S, where the C-terminal domain (CTD) interacts with eIF4A at the mRNA entry site, while the N-terminal domain (NTD) is inserted into the mRNA channel and decoding site. The structures, together with quantitative binding and in vitro translation assays, shed light on the critical role of the NTD for the recruitment of Pdcd4 to the ribosomal complex and suggest a model whereby Pdcd4 blocks the eIF4F-independent role of eIF4A during recruitment and scanning of the 5' UTR of mRNA.

biochemistry↗

bioRxiv2018

ECM deposition is driven by caveolin1-dependent regulation of exosomal biogenesis and cargo sorting

The composition and physical properties of the extracellular matrix (ECM) critically influence tumour cell behaviour, and ECM deposition and remodelling by stromal fibroblast populations is therefore pivotal for tumour progression. The molecular mechanisms by which stromal and tumour cell populations regulate ECM layering are poorly understood. Tumour-stroma interaction is critically dependent on cell-cell communication mediated by exosomes, small vesicles secreted by most cell types and generated within multivesicular bodies (MVBs). Here, we show that caveolin-1 (Cav1), an essential regulator of stromal remodelling and tumour cell fate, plays a central role in modulating both exosome biogenesis and exosomal protein cargo sorting through cholesterol-dependent mechanisms. Quantitative proteomics profiling revealed that a major share of Cav1-dependent exosomal cargoes are compsed of ECM proteins, one of the most important components being tenascin-C (TnC). Comparative functional assays demonstrated that Cav1 is required for fibroblast-derived exosomes to depose ECM and promote tumour cell invasiveness. Exosomes purified from Cav1WT cells, but not those from Cav1-null cells, were able to nucleate distant stromal niches in different organs in vivo. These findings suggest a key role for Cav1 as a cholesterol rheostat in MVBs, and seems to determine ECM deposition by eliciting ECM component sorting into specific exosome pools. These results, together with previous work, support a model in which Cav1 is a central regulatory hub for tumour-stroma interactions through a novel exosome-dependent ECM deposition mechanism.

cell biology↗