bims-lycede 2025-03-02 papers

EMBO Rep. 2025 Feb 27.

The spectrum of lysosomal stress and damage responses: from mechanosensing to inflammation.

Ori Scott, Ekambir Saran, Spencer A Freeman.

Cells and tissues turn over their aged and damaged components in order to adapt to a changing environment and maintain homeostasis. These functions rely on lysosomes, dynamic and heterogeneous organelles that play essential roles in nutrient redistribution, metabolism, signaling, gene regulation, plasma membrane repair, and immunity. Because of metabolic fluctuations and pathogenic threats, lysosomes must adapt in the short and long term to maintain functionality. In response to such challenges, lysosomes deploy a variety of mechanisms that prevent the breaching of their membrane and escape of their contents, including pathogen-associated molecules and hydrolases. While transient permeabilization of the lysosomal membrane can have acute beneficial effects, supporting inflammation and antigen cross-presentation, sustained or repeated lysosomal perforations have adverse metabolic and transcriptional consequences and can lead to cell death. This review outlines factors contributing to lysosomal stress and damage perception, as well as remedial processes aimed at addressing lysosomal disruptions. We conclude that lysosomal stress plays widespread roles in human physiology and pathology, the understanding and manipulation of which can open the door to novel therapeutic strategies.

Keywords: Autophagy; Glycocalyx; Host–pathogen; Phagosolysosome; Pore-forming Toxins

DOI: https://doi.org/10.1038/s44319-025-00405-9

Am J Respir Cell Mol Biol. 2025 Feb 25.

TFEB SUMOylation in Airway Epithelial Cells Impairs Lysosomal Biogenesis to Promote Asthma Development.

Qianying Yu, Yao Zhou, Jing Wang, Meng Zhang, Caixia Di, Yujiao Wu, Qun Wu, Wen Su, Jinke Cheng, Jiajia Lv, Min Wu, Zhenwei Xia.

Lysosomal dysfunction is the primary cause of various immune disorders. Transcription factor EB (TFEB) SUMOylation is critically involved in the lysosomal biogenesis. Whether TFEB SUMOylation-associated lysosomal dysfunction contributes to asthma pathogenesis remain to be determined. Here, we observed that ovalbumin (OVA)-stimulation impaired lysosomal function through TFEB SUMOylation, which leads to increased NLRP3 and inflammatory factors. Mechanistically, mutation of TFEB SUMOylation site did not abolish the ability of its nuclear translocation, but increased TFEB stability and binding capability with target genes' promoters, thereby promoting lysosomal biogenesis and bioactivity through liquid-liquid phase separation (LLPS), and thus inhibiting the production of inflammatory factors and alleviating allergic airway inflammation. Our observations demonstrate that TFEB SUMOylation interferes with lysosomal biogenesis contributing to asthma pathogenesis, lending mechanistic insight into asthmatic disease and improving our understanding of the transcriptional regulation of host immune responses.

Keywords: NLRP3 inflammasome; SUMO1; TFEB; epithelial cells; lysosomes

DOI: https://doi.org/10.1165/rcmb.2024-0191OC

Nat Commun. 2024 Dec 30. 15(1): 10829

Spatiotemporal proteomics reveals the biosynthetic lysosomal membrane protein interactome in neurons.

Chun Hei Li, Noortje Kersten, Nazmiye Özkan, Dan T M Nguyen, Max Koppers, Harm Post, Maarten Altelaar, Ginny G Farias.

Lysosomes are membrane-bound organelles critical for maintaining cellular homeostasis. Delivery of biosynthetic lysosomal proteins to lysosomes is crucial to orchestrate proper lysosomal function. However, it remains unknown how the delivery of biosynthetic lysosomal proteins to lysosomes is ensured in neurons, which are highly polarized cells. Here, we developed Protein Origin, Trafficking And Targeting to Organelle Mapping (POTATOMap), by combining trafficking synchronization and proximity-labelling based proteomics, to unravel the trafficking routes and interactome of the biosynthetic lysosomal membrane protein LAMP1 at specified time points. This approach, combined with advanced microscopy, enables us to identify the neuronal domain-specific trafficking machineries of biosynthetic LAMP1. We reveal a role in replenishing axonal lysosomes, in delivery of newly synthesized axonal synaptic proteins, and interactions with RNA granules to facilitate hitchhiking in the axon. POTATOMap offers a robust approach to map out dynamic biosynthetic protein trafficking and interactome from their origin to destination.

DOI: https://doi.org/10.1038/s41467-024-55052-w

J Mol Biol. 2025 Feb 22. pii: S0022-2836(25)00101-9. [Epub ahead of print] 169035

Lysosomal degradation of ER client proteins by ER-phagy and related pathways.

Carla Salomo-Coll, Natalia Jimenez-Moreno, Simon Wilkinson.

The endoplasmic reticulum (ER) is a major site of cellular protein synthesis. Degradation of overabundant, misfolded, aggregating or unwanted proteins is required to maintain proteostasis and avoid the deleterious consequences of aberrant protein accumulation, at a cellular and organismal level. While extensive research has shown an important role for proteasomally-mediated, ER-associated degradation (ERAD) in maintaining proteostasis, it is becoming clear that there is a substantial role for lysosomal degradation of "client" proteins from the ER lumen or membrane (ER-to-lysosome degradation, ERLAD). Here we provide a brief overview of the broad categories of ERLAD - predominantly ER-phagy (ER autophagy) pathways and related processes. We collate the client proteins known to date, either individual species or categories of proteins. Where known, we summarise the molecular mechanisms by which they are selected for degradation, and the setting in which lysosomal degradation of the client(s) is important for correct cell or tissue function. Finally, we highlight the questions that remain open in this area.

DOI: https://doi.org/10.1016/j.jmb.2025.169035

Biosens Bioelectron. 2025 Feb 19. pii: S0956-5663(25)00159-9. [Epub ahead of print]277 117285

A "turn-on" intracellular pH probe for the quantitative monitoring of lysosomal alkalization in living cells.

Hejian Ke, Jiaqi Yang, Wanping Zhang, Pengli Yang, Yiwu Wang, Ningrong Wang, Jiahao Bai, Huaiyi Yin, Yanyan Chen, Xinhong Chen, Peishan Fu, Yongjun Gan, Guangchao Zang, Qian Liu.

A slight elevation in lysosomal pH can lead to indigestion or nonspecific hydrolysis, thereby increasing the risk of various neurodegenerative diseases and cancer. Therefore, accurate monitoring of lysosomal pH changes in living cells is essential for the diagnosis and treatment of such diseases, despite the significant challenges involved. In this study, we synthesized a pH-dependent fluorescent probe, B26, which comprises 1,8-naphthalimide as the fluorescent chromophore, an N-(2-hydroxyethyl) piperazine group for lysosome targeting, and a hydroxyethyl group to increase solubility and regulate pKa. B26 demonstrated high sensitivity, selectivity, and reversibility in response to H+, and exhibited a remarkable 98-fold increase in fluorescence intensity between pH 2.0 and pH 11.0, with a pKa value of 7.0, highlighting its "turn-on" fluorescence property. Density functional theory calculations and 1H NMR titration revealed that the pH-sensing mechanism of B26 relies on the inhibition of photoinduced electron transfer from the N-(2-hydroxyethyl) piperazine group to the naphthalimide moiety under acidic conditions. Importantly, B26 effectively labeled lysosomes and displayed significant sensitivity to pH changes, facilitating the quantitative detection of pH shifts during lysosomal alkalization in living cells due to its elevated pKa. These findings suggest that B26 successfully addresses the limitations of existing lysosomal pH probes, particularly in detecting pH changes within the near-neutral range. Furthermore, both the zebrafish model and subcutaneous imaging support the application of B26 in in vivo settings. Given its exceptional properties, B26 holds enormous potential for the research and diagnosis of pH-related diseases.

Keywords: Fluorescence probe; Living cell imaging; Lysosomal alkalization; Lysosomal pH monitoring; pH sensing

DOI: https://doi.org/10.1016/j.bios.2025.117285

Neural Regen Res. 2025 Feb 24.

Stress granules: guardians of cellular health and triggers of disease.

Meghal Desai, Keya Gulati, Manasi Agrawal, Shruti Ghumra, Pabitra K Sahoo.

ABSTRACT: Stress granules are membraneless organelles that serve as a protective cellular response to external stressors by sequestering non-translating messenger RNAs (mRNAs) and regulating protein synthesis. Stress granules formation mechanism is conserved across species, from yeast to mammals, and they play a critical role in minimizing cellular damage during stress. Composed of heterogeneous ribonucleoprotein complexes, stress granules are enriched not only in mRNAs but also in noncoding RNAs and various proteins, including translation initiation factors and RNA-binding proteins. Genetic mutations affecting stress granule assembly and disassembly can lead to abnormal stress granule accumulation, contributing to the progression of several diseases. Recent research indicates that stress granule dynamics are pivotal in determining their physiological and pathological functions, with acute stress granule formation offering protection and chronic stress granule accumulation being detrimental. This review focuses on the multifaceted roles of stress granules under diverse physiological conditions, such as regulation of mRNA transport, mRNA translation, apoptosis, germ cell development, phase separation processes that govern stress granule formation, and their emerging implications in pathophysiological scenarios, such as viral infections, cancer, neurodevelopmental disorders, neurodegeneration, and neuronal trauma.

DOI: https://doi.org/10.4103/NRR.NRR-D-24-01196