Biology subjects

Solda, T.

Publications and source records attributed to Solda, T..

4 recordsLinked to original sources

bioRxiv2026

Epstein Barr virus exploits ER stress and TMX4 dependent nuclear envelope remodeling to enable capsid egress

Herpesvirus capsids assemble within the nucleoplasm of infected cells in highly ordered icosahedral structures with a diameter of about 100nm. Despite the small distance between outer and inner nuclear membrane, which is fixed between the 25 and the 50nm by disulfide bonded LINC complexes, the capsid particles cross the barrier and are delivered into the cytoplasm, where viral particle assembly continues. How Epstein-Barr virus (EBV) overcomes the spatial constraints imposed by the narrow perinuclear space for nuclear egress of the viral capsids remains unclear. Here, we show that EBV exploits an ER-stress-responsive nuclear envelope (NE) remodeling pathway to promote capsid egress. Induction of EBV lytic replication activates the IRE1 branch of the unfolded protein response and triggers TMX4-dependent remodeling of the NE. Inhibition of IRE1 signaling or depletion of TMX4 prevents efficient redistribution of viral capsid proteins from the nucleus to the cytoplasm, causes accumulation of unused viral glycoprotein GP350 in Golgi-derived membranes, and markedly reduces production of infectious viral particles. Thus, EBV hijacks a host NE adaptation pathway to overcome a fundamental physical barrier during viral maturation.

cell biology↗

bioRxiv2024

A novel class of allosteric glucosylceramidase beta 1 correctors that reduce cellular stress and enhance lysosomal function

Mutations in glucosylceramidase beta 1 (GCase) disrupt the proteins conformational maturation in the endoplasmic reticulum (ER) and hinder its transport to the lysosome. The intralysosomal accumulation of glucocerebrosides, which are substrates of the GCase enzyme, impairs lysosomal function and is linked to Gaucher disease (GD). GCase mutations also increase the risk of Parkinsons disease (PD) and Dementia with Lewy Bodies. We used Site-directed Enzyme Enhancement Therapy (SEE-Tx(R)) technology to design two structurally targeted allosteric regulators (STARs) of GCase. Administration of GT-02287 and GT-02329 to cultured GD patient-derived primary human fibroblasts enhances folding and protects the two most common disease-causing GCase variants, GCaseAsn370Ser and GCaseLeu444Pro, from proteasomal degradation. Mechanistically, these treatments facilitate the lysosomal delivery of enzymatically active forms of mutant GCase, leading to improved lysosomal function and reduced cellular stress in GD patient-derived fibroblasts. The findings suggest that the allosteric pharmacologic regulators GT-02287 and GT-02329 hold promise for further development as potential therapeutic agents for GCase-related disorders, including GD, PD and Dementia with Lewy Bodies.

cell biology↗

bioRxiv2024

TMX5/TXNDC15, a natural trapping mutant of the PDI family is a client of the proteostatic factor ERp44

The endoplasmic reticulum (ER) is the organelle of nucleated cells that produces lipids, sugars and proteins. More than 20 ER-resident members of the Protein Disulfide Isomerase (PDI) family regulate formation, isomerization and disassembly of covalent bonds in newly synthesized polypeptides. The PDI family includes few membrane-bound members. Among these, TMX1, TMX2, TMX3, TMX4 and TMX5 belong to the thioredoxin-related transmembrane (TMX) protein family. TMX5 is the least known member of the family. Here, we establish that TMX5 covalently engages via its active site cysteine residue at position 220 a subset of secretory proteins, mainly single- and multi-pass Golgi-resident polypeptides. TMX5 also interacts non-covalently, and covalently, via non-catalytic cysteine residues, with the PDI family members PDI, ERp57 and ERp44. The association of TMX5 and ERp44 requires formation of a mixed disulfide between the catalytic cysteine residue 29 of ERp44 and the non-catalytic cysteine residues 114 and/or 124 of TMX5 and controls the ER retention of TMX5. Thus, TMX5 belongs to the family of proteins including Ero1, Ero1{beta}, Prx4, ERAP1, SUMF1 that do not display ER retention sequences and rely on ERp44 engagement for proper inter-compartmental distribution.

cell biology↗

bioRxiv2022

SEC62 and TMX4 control asymmetric autophagy of the nuclear envelope upon LINC complex disassembly

The endoplasmic reticulum (ER) is a dynamic organelle of nucleated cells that produces proteins, lipids and oligosaccharides. The volume and the activities of the ER are adapted to cellular needs. They are increased upon induction of unfolded protein responses (UPR 1) and are reduced upon activation of ER-phagy programs 2. A specialized domain of the ER, the nuclear envelope (NE), protects the cell genome with two juxtaposed lipid bilayers, the inner and outer nuclear membranes (INM and ONM). SUN proteins in the INM form disulfide-bonded Linker of Nucleoskeleton and Cytoskeleton (LINC) complexes with NESPRIN proteins in the ONM. These complexes set and maintain the width of the periplasmic space (PS), a continuum of the ER lumen, below the 50 nm 3-5 and in yeast prevent transmission of ER volume variations to the PS 6,7. Here we report that expansion of the mammalian ER upon homeostatic perturbations is transmitted to the NE, where the ONM forms large bulges. The process is reverted on recovery of ER homeostasis, by asymmetric vesiculation and autophagic clearance of ONM portions. Remodeling of the mammalian NE requires TMX4-driven reduction of the intermolecular disulfide bond stabilizing LINC complexes, the LC3 lipidation machinery, and the autophagy receptor SEC62, identified here as the first mammalian nucleo-phagy receptor.

cell biology↗