Biology subjects

Padovano, V.

Publications and source records attributed to Padovano, V..

6 recordsLinked to original sources

bioRxiv2026

A cargo receptor entrapment complex is a therapeutic node for genetically and clinically distinct proteinopathies

Severe proteinopathies--such as retinitis pigmentosa, a form of inherited blindness--are driven by genetic mutations that overwhelm the quality control of the post-endoplasmic reticulum (post-ER) secretory pathway, causing toxic protein accumulation. Here, we identify a therapeutic node defined by a hetero-oligomeric cargo receptor complex consisting of TMED7, 2, 9, and 10. This "entrapment complex" anchors structurally and functionally diverse mutant clients within the early secretory pathway via TMED7 binding to the integral Golgi protein GRASP55. Disruption of the entrapment complex results in the clearance of accumulated protein cargoes. In vivo ablation of the entrapment node via inducible genetic deletion or via the small molecule BRD7635 reverses histopathological hallmarks and rescues functional deficits in clinically distinct proteinopathies of the kidney and the eye, including mitigating vision loss in a mouse model of retinitis pigmentosa.

cell biology↗

bioRxiv2026

Neuronal late endosomes serve as selective RNA hubs disrupted by ALS-linked FUS mutation

Neurons depend on tightly regulated positioning of cellular components to maintain long-distance signaling, but the mechanisms guiding specific mRNAs to distant regions remain unclear. Here we show that late endosomes function as selective RNA carriers in human motor neurons and uncover the molecular logic guiding their loading. Using APEX2-mediated proximity labeling, we identify the external transcriptome of RAB7A-positive endosomes and find a specific population of mRNAs enriched for endosomal, axonal and synaptic functions. We find that mRNAs enriched in RAB7A endosomes contain evolutionarily conserved 5'UTRs which act as localization signals, and that the RNA-binding protein GEMIN5 interacts with these regions to promote endosomal RNA recruitment. Finally, we show that in ALS-associated conditions there is a conspicuous loss of endosome-associated transcripts and the mislocalization of GEMIN5 from endosomes. These findings uncover fundamental principles of RNA compartmentalization and highlight endosomal mRNA loading as a vulnerable axis in neuronal homeostasis.

molecular biology↗

bioRxiv2025

Polycystin-1 acts as an atypical adhesion GPCR that responds to novel Wnt signaling and mechanical stimuli

Mutations in the genes encoding Polycystin-1 and 2 cause autosomal dominant polycystic kidney disease (ADPKD). These proteins cellular functions and the mechanisms through which their absence causes disease are unknown. We find that the behavior of the 11 transmembrane domain polycystin-1 protein resembles that of an adhesion G protein-coupled receptor when activated by Wnt ligands. Exposure to Wnt ligands causes shedding of the polycystin-1 N terminal region, exposing a tethered agonist that activates G protein-dependent functions of the membrane-associated C terminal fragment. Activated polycystin-1 communicates through G13 to activate RhoA, leading in turn to the ROCK-dependent phosphorylation and inactivation of GSK3{beta}. Activated polycystin-1 traffics out of the primary cilium through an arrestin-dependent mechanism, and arrestin involvement is required for signaling to occur. These data elaborate a function for polycystin-1 that is structurally non-canonical and that is directly connected to pathways whose perturbation results in cystic disease. SummaryThe polycystin-1 protein can activate a signaling pathway resembling those employed by non-canonical adhesion G protein coupled receptors, which is induced by Wnt9b binding and which leads to leads to inhibition of the GSK3{beta} kinase and removal of polycystin-1 from the primary cilium. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/655326v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@1b32dc1org.highwire.dtl.DTLVardef@80ee43org.highwire.dtl.DTLVardef@9aa441org.highwire.dtl.DTLVardef@95ceb1_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract PC1 resides at baseline in the primary cilium. PC1 behaves as an aGPCR that responds to Wnt9b and to flow-induced ATP release by departing from the cilium and initiating the inhibition of GSK3. The schematic diagram presents a model that integrates the findings presented here. Wnt9b binding to the PC1 NTF leads to shedding of the NTF, exposing the tethered agonist to activate the PC1 receptor-mediated signaling cascade, which involves triggering G13 binding and the subsequent nucleotide exchange and GTP-loading of RhoA. GTP-bound RhoA stimulates the kinase activity of ROCK, which phosphorylates and inhibits GSK3. C_FIG

cell biology↗

bioRxiv2021

The C-terminal tail of polycystin-1 suppresses cystic disease in a mitochondrial enzyme-dependent fashion

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent potentially lethal monogenic disorder. Approximately 78% of cases are caused by mutations in the PKD1 gene, which encodes polycystin-1 (PC1). PC1 is a large 462-kDa protein that undergoes cleavage in its N and C-terminal domains. C-terminal cleavage produces fragments that translocate to mitochondria. We show that transgenic expression of a protein corresponding to the final 200 amino acid residues of PC1 in a Pkd1-KO orthologous murine model of ADPKD dramatically suppresses cystic phenotype and preserves renal function. This suppression depends upon an interaction between the C-terminal tail of PC1 and the mitochondrial enzyme Nicotinamide Nucleotide Transhydrogenase. This interaction modulates tubular/cyst cell proliferation, the metabolic profile, mitochondrial function and the redox state. Together, these results suggest that a short fragment of PC1 is sufficient to suppress cystic phenotype and open the door to the exploration of gene therapy strategies for ADPKD.

physiology↗

bioRxiv2020

A High Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury during the COVID-19 pandemic

Drug repurposing is the only method capable of delivering treatments on the shortened time-scale required for patients afflicted with lung disease arising from SARS-CoV-2 infection. Mucin-1 (MUC1), a membrane-bound molecule expressed on the apical surfaces of most mucosal epithelial cells, is a biochemical marker whose elevated levels predict the development of acute lung injury (ALI) and respiratory distress syndrome (ARDS), and correlate with poor clinical outcomes. In response to the pandemic spread of SARS-CoV-2, we took advantage of a high content screen of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that reduce MUC1 protein abundance. Our screen identified Fostamatinib (R788), an inhibitor of spleen tyrosine kinase (SYK) approved for the treatment of chronic immune thrombocytopenia, as a repurposing candidate for the treatment of ALI. In vivo, Fostamatinib reduced MUC1 abundance in lung epithelial cells in a mouse model of ALI. In vitro, SYK inhibition by Fostamatinib promoted MUC1 removal from the cell surface. Our work reveals Fostamatinib as a repurposing drug candidate for ALI and provides the rationale for rapidly standing up clinical trials to test Fostamatinib efficacy in patients with COVID-19 lung injury.

cell biology↗

bioRxiv2019

Single Cell RNAseq Reveals A Critical Role of Chloride Channels in Airway Development

The conducting airway forms a protective mucosal barrier and is the primary target of airway disorders. To better understand how airway developmental programs are established to support air breathing and barrier functions, we constructed a single-cell atlas of the human and mouse developing trachea. In this study, we uncover hitherto unrecognized heterogeneity of cell states with distinct differentiation programs and immune features of the developing airway. In addition, we find ubiquitous expression of CFTR and ANO1/TMEM16A chloride channels in the embryonic airway epithelium. We show that genetic inactivation of TMEM16A leads to airway defects commonly seen in cystic fibrosis patients with deficient CFTR, alters the differentiation trajectory of airway basal progenitors, and results in mucus cell hyperplasia and aberrant epithelial antimicrobial expression. Together, our study illuminates conserved developmental features of the mammalian airway and implicates chloride homeostasis as a key player in regulating mucosal barrier formation and function relevant to early onset airway diseases.

developmental biology↗