bims-lycede 2026-01-04 papers

Traffic. 2026 Mar;27(1): e70026

Unraveling Lysosomal Exocytosis: From Molecular Mechanisms to Physiological Functions.

Shanshan Jiang, Jingyi Fu, Shan Li, Zehui Li, Qirui Zhao, Yuqi Yin, Mei Yang, Yonghua Wang.

Lysosomal exocytosis is a fundamental cellular process that involves the fusion of lysosomes with the plasma membrane and the release of lysosomal contents into the extracellular space. This review provides an in-depth analysis of the molecular mechanisms, physiological functions, and disease implications of lysosomal exocytosis, highlighting recent advances and novel aspects. We discuss the intricate molecular machinery that orchestrates lysosomal trafficking, docking, and fusion, as well as the critical roles of lysosomal exocytosis in maintaining cellular homeostasis, facilitating intercellular communication, and contributing to specialized cellular functions. Additionally, the review explores the complex involvement of lysosomal exocytosis in various disease states, including lysosomal storage disorders, neurodegenerative diseases, cancers, and immune system disorders, underlining its potential as a therapeutic target. By identifying current knowledge gaps and providing future research directions, this review aims to stimulate further investigation into the multifaceted nature of lysosomal exocytosis and its implications for human health and disease.

DOI: https://doi.org/10.1111/tra.70026

Cell Res. 2026 Jan 02.

Repair of damaged lysosomes by TECPR1-mediated membrane tubulation during energy crisis.

Hanmo Chen, Chaojun Zhang, Yuhui Fu, Linsen Li, Xiaoyu Qiao, Shen Zhang, Hanyan Luo, She Chen, Xiaoxia Liu, Qing Zhong.

Lysosomes are essential for cellular homeostasis, serving as degradative organelles that recycle nutrients. Whether and how lysosomes maintain membrane integrity under energy stress is poorly understood. Here, we found that the uptake of lipid droplets by lysosomes during glucose starvation provokes disruption of lysosomal membranes. We identified tectonin beta-propeller repeat-containing protein 1 (TECPR1) as a critical mediator of lysosomal repair during glucose starvation or LLOMe-induced lysosomal membrane permeabilization. TECPR1 is recruited to damaged lysosomes via interaction with PI4P on damaged lysosomal membranes. It interacts with KIF1A to facilitate tubule formation from damaged lysosomes, enabling the removal of damaged membrane components and promoting lysosomal repair. Our in vitro reconstituted tubulation process provided further evidence that TECPR1 coordinates with KIF1A to drive tubulation from PI4P-enriched giant unilamellar vesicles. TECPR1-mediated lysosomal repair is essential for maintaining lipid metabolism and cellular survival during an energy crisis, as TECPR1 deficiency exacerbates starvation-induced liver damage in a high-fat diet-induced MAFLD mouse model. Our findings demonstrate a previously unrecognized role of TECPR1 in lysosomal repair, revealing its critical contributions to energy stress adaptation and liver protection. This work provides new insight into mechanisms of lysosomal repair and their implications for metabolic and lysosome-related disorders.

DOI: https://doi.org/10.1038/s41422-025-01193-6

Autophagy. 2025 Dec 31.

A novel mechanism of lysosome-dependent microautophagy of er exit sites.

Dibyendu Bhattacharyya, Daniel J Klionsky.

Endoplasmic reticulum (ER) exit sites (ERES) serve as essential hubs for the packaging and export of secretory proteins into the COPII vesicular pathway. Previous studies have shown that ERES are dynamic and capable of adapting to stress, but the molecular details controlling their degradation under nutrient stress conditions were largely unknown. The study by Liao et al. (2024) introduces a new mechanism in which ERES are degraded through lysosome-dependent microautophagy in response to nutrient stress. This process is uniquely facilitated by COPII components, the calcium-binding adaptor ALG2, and the ESCRT machinery. The authors demonstrate that inhibiting MTOR triggers calcium release from lysosomes, which then recruits ALG2, leading to SEC31 ubiquitination and subsequently promoting PDCD6IP/ALIX-ESCRT-dependent lysosomal engulfment of ERES. This research reveals an unexplored pathway for the quality control and recycling of secretory machinery, thereby improving our understanding of ER turnover and establishing a mechanistic link between nutrient sensing, autophagy, and remodeling of the secretory pathway.

Keywords: Autophagy; COPII; ESCRT; er exit sites; microautophagy

DOI: https://doi.org/10.1080/15548627.2025.2608387

Sci Adv. 2026 Jan 02. 12(1): eaea9302

TFEB coordinates autophagosome biogenesis and ribophagy during starvation via SQSTM1.

Maria Iavazzo, Laura Cinque, Sophie Levantovsky, Castrese Morrone, Jlenia Monfregola, Andrea Raimondi, Elena Polishchuk, Rossella De Cegli, Diego Carrella, Edoardo Nusco, Luigi Ferrante, Francesca Sacco, Lisa B Frankel, Christian Behrends, Carmine Settembre.

(Macro)autophagy is a conserved cellular degradation pathway that delivers substrates to lysosomes via autophagosomes. Among various physiological stimuli, nutrient starvation is the most potent inducer of autophagy. In response to starvation, transcription factor EB (TFEB) is activated and up-regulates a broad set of autophagy-related genes. However, the mechanisms by which TFEB promotes autophagosome biogenesis remain incompletely understood. Here, we demonstrate that TFEB-mediated transcriptional induction of sequestosome 1 (SQSTM1; p62) triggers the formation of SQSTM1-positive bodies that recruit essential autophagy factors, thereby initiating autophagosome biogenesis. Genetic disruption of TFEB-dependent SQSTM1 regulation markedly impairs starvation-induced autophagy, underscoring the critical role of the TFEB-SQSTM1 axis in the autophagic response to nutrient stress. Furthermore, we show that these SQSTM1 bodies contain ubiquitinated ribosomal proteins and that TFEB promotes ribosomal protein ubiquitination by inducing the E3 ubiquitin ligase ZNF598. Collectively, our findings uncover a transcriptionally coordinated mechanism that regulates both autophagosome biogenesis and substrate ubiquitination, facilitating efficient cargo clearance during starvation-induced autophagy.

DOI: https://doi.org/10.1126/sciadv.aea9302

PLoS Genet. 2025 Dec 31. 21(12): e1011607

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

Győző Szenci, Attila Boda, Anikó Nagy, Dorottya Károlyi, András Rubics, Zsombor Szőke, Gergő Falcsik, Tibor Kovács, Péter Lőrincz, Gábor Juhász, Szabolcs Takáts.

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 Huntington's 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 morphology 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 propose that ankyrin repeat palmitoyl transferases 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 Huntington's disease-like symptoms.

DOI: https://doi.org/10.1371/journal.pgen.1011607