Biology subjects

Lorincz, P.

Publications and source records attributed to Lorincz, P..

5 recordsLinked to original sources

bioRxiv2026

SERCA is a host target of the SARS-CoV-2 envelope protein linking calcium homeostasis to autophagy

The SARS-CoV-2 envelope (E) protein is a virulence factor that remodels host endomembranes, but mechanisms remain incompletely understood. We recently demonstrated that E protein interacts with and inhibits the sarco/endoplasmic reticulum Ca2-ATPase (SERCA), disrupting ER calcium homeostasis. Here, we investigated how this perturbation affects autophagy-associated membrane organization. E protein expression induced lipidated LC3 accumulation and enlarged p62-positive structures, consistent with dysregulated autophagic turnover. Although E protein partially colocalized with LC3 and p62, enlarged p62-positive structures were also observed in cells retaining the reticular ER distribution of E protein, indicating that their formation does not require association with E protein or ER reorganization. E protein also increased the association of p62-positive structures with lysosomes without altering lysosome abundance. Pharmacological SERCA activation attenuated E protein-induced remodeling of autophagy-associated structures, demonstrating that SERCA inhibition contributes to these alterations. Together, our findings establish SERCA-dependent ER calcium homeostasis as a host pathway linking E protein expression to remodeling of autophagy-associated membrane compartments, providing a mechanistic framework for how the SARS-CoV-2 E protein promotes ER membrane remodeling associated with coronavirus replication.

cell biology↗

bioRxiv2026

Multiple overlapping SNARE complexes drive endosome maturation in Drosophila nephrocytes

Endosomal maturation determines whether internalized cargo is recycled or degraded, yet the molecular logic governing early endosomal fusion remains poorly defined. This process is often depicted as a linear Rab5-to-Rab7 transition mediated by a single, ordered SNARE pathway, but extensive redundancy in mammalian systems has obscured pathway architecture. Here, using Drosophila nephrocytes as a genetically tractable in vivo model with minimal SNARE redundancy, we show that early endosome maturation is driven by multiple parallel, non-interchangeable SNARE-dependent pathways. We first resolve a long-standing discrepancy in Syntaxin 7 family orthology, demonstrating that the Drosophila protein previously termed Syx7/Avl is functionally analogous to mammalian STX12 rather than STX7, while late endosomal and lysosomal fusion is mediated by a distinct Syntaxin 7 homolog (Syx13). Based on this reclassification, we define a Syx12L-Snap29-Ykt6 complex that drives canonical homotypic early endosomal fusion. In addition, we identify two related SNARE assemblies - Syx7L-Snap29-Ykt6 and Syx7L-Snap29-Vamp7-that promote later stages of endosomal and lysosomal fusion with distinct Rab GTPase requirements. These partially compensatory complexes remain active when the canonical pathway is disrupted, producing divergent morphological outcomes, including the formation of aberrant endolysosomal swirls. We establish Snap29 as a central Qbc-SNARE integrating all endosomal fusion routes and uncover a dual role for Ykt6 in promoting maturation while also participating in endosomal recycling. Together, our findings revise the prevailing model of endosome maturation, revealing a network of parallel, regulated fusion pathways that confer robustness and plasticity to the endolysosomal system.

cell biology↗

bioRxiv2025

Huntington's disease-associated ankyrin repeat palmitoyl transferases are rate-limiting factors in lysosome formation and fusion

Protein palmitoylation in the Golgi apparatus is critical for the appropriate sorting of various proteins belonging to secretory and lysosomal systems, and defective palmitoylation can lead to the onset of severe pathologies. HIP14 and HIP14L ankyrin repeat-containing palmitoyl transferases were linked to the pathogenesis of Huntingtons disease, however, how perturbation of these Golgi resident enzymes contributes to neurological disorders is yet to be understood. In this study, we investigated the function of Hip14 and Patsas - the Drosophila orthologs of HIP14 and HIP14L respectively - to uncover their role in secretory and lysosomal membrane trafficking. Using larval salivary gland, a well-established model of the regulated secretory pathway, we found that these PAT enzymes equally contribute to the proper maturation and crinophagic degradation of glue secretory granules by mediating their fusion with the endo-lysosomal compartment. We also revealed that Patsas and Hip14 are both required for lysosomal acidification and biosynthetic transport of various lysosomal hydrolases, and we demonstrated that the rate of secretory granule-lysosome fusion and subsequent acidification positively correlates with the level of Hip14. Furthermore, Hip14 is also essential for proper lysosome formation and neuronal function in adult brains. Finally, we found that the over-activation of lysosomal biosynthetic transport and lysosomal fusions by the expression of the constitutively active form of Rab2 could compensate for the lysosomal dysfunction caused by the loss of Patsas or Hip14 both in larval salivary glands and neurons. Therefore, we demonstrated that ankyrin repeat palmitoyl transferases may act as rate-limiting factors in lysosomal fusions and provide genetic evidence that defective protein palmitoylation and the subsequent lysosomal dysfunction can contribute to the onset of Huntingtons disease-like symptoms. Author SummaryGrowing body of evidence suggests that decreased activity of HIP14 and HIP14L palmitoyl transferases caused by accumulation of mutant Huntingtin and the subsequent alterations in protein palmitoylation play a critical role in the onset of Huntingtons disease (HD). However, which cellular processes are perturbed and eventually lead to the emergence of HD due to impaired palmitoylation is still poorly understood. In our study, we used a Drosophila model to uncover the role of Hip14 and Patsas (the fly ortholog of HIP14L) in secretory and lysosomal membrane trafficking. We found that silencing of these transferases in larval salivary glands equally disrupts secretory granule lysosome-fusion, their subsequent acidification and also the trafficking of lysosomal hydrolases. While overexpression of Hip14 resulted in the acceleration of these processes. We also observed that neuron-specific loss of Hip14 not only perturbs lysosome formation but also results in a progressive decline in neuromuscular functions. Importantly, both lysosomal and neuronal defects emerging in Hip14 and Patsas deficient backgrounds could be restored by hyperactivation of Rab2 GTPase mediated lysosome formation and fusion. These findings suggest that Hip14 and Patsas protect from the onset of HD like symptoms by acting as rate-limiting factors of lysosome formation and fusion.

cell biology↗

bioRxiv2024

A "torn bag mechanism" of small extracellular vesicle release via limiting membrane rupture of en bloc released amphisomes (amphiectosomes)

Recent studies showed an unexpected complexity of extracellular vesicle (EV) biogenesis pathways. We previously found evidence that human colorectal cancer cells in vivo release large multivesicular body-like structures en bloc. Here, we tested whether this large extracellular vesicle type is unique to colorectal cancer cells. We found that all cell types we studied (including different cell lines and cells in their original tissue environment) released multivesicular large EVs (MV-lEVs). We also demonstrated that upon spontaneous rupture of the limiting membrane of the MV-lEVs, their intraluminal vesicles (ILVs) escaped to the extracellular environment by a "torn bag mechanism". We proved that the MV-lEVs were released by ectocytosis of amphisomes (hence, we termed them amphiectosomes). Both ILVs of amphiectosomes and small EVs separated from conditioned media were either exclusively CD63 or LC3B positive. According to our model, upon fusion of multivesicular bodies with autophagosomes, fragments of the autophagosomal inner membrane curl up to form LC3B positive ILVs of amphisomes, while CD63 positive small EVs are of multivesicular body origin. Our data suggest a novel common release mechanism for small EVs, distinct from the exocytosis of multivesicular bodies or amphisomes, as well as the small ectosome release pathway.

cell biology↗

bioRxiv2020

Vps13D is required for mitochondrial fission and mitophagy triggered by fission defects in Drosophila neurons

A healthy population of mitochondria, maintained by proper fission, fusion, and degradation, is critical for the long-term survival and function of neurons. Here, our discovery of mitophagy intermediates in fission-impaired Drosophila neurons brings new perspective into the relationship between mitochondrial fission and mitophagy. Neurons lacking either the ataxia disease gene Vps13D or the dynamin related protein Drp1 contain enlarged mitochondria that are engaged with autophagy machinery and also lack matrix components due to rupture. Reporter assays combined with genetic studies imply that mitophagy both initiates and is completed in Drp1 impaired neurons, but fails to complete in Vps13D impaired neurons, which accumulate compromised mitochondria within stalled mito-phagophores. Our findings imply that in fission-defective neurons, mitophagy becomes induced, and that the lipid channel containing protein Vps13D has separable functions in mitochondrial fission and phagophore elongation.

cell biology↗