bims-lycede 2025-06-29 papers

Mol Cell Biol. 2025 Jun 22. 1-10

Nuclear Roles for Canonically Lysosomal Proteases.

Anna E Enneking, Marc M Khorey, Laura E Edgington-Mitchell.

While the cysteine proteases legumain and cathepsins have traditionally been known as "lysosomal" proteases, there is increasing evidence to suggest that they also contribute to a wide range of extralysosomal processes, including in the nucleus. This review aims to provide a comprehensive overview of the current knowledge regarding the translocation of these proteases to the nucleus and their functions on arrival. We discuss possible mechanisms for transporting these proteases to the nucleus, including the presence of a nuclear localization signal sequence or hitchhiking on other proteins that possess this sequence. This transport requires the proteases to first reach the cytosol, which may occur via direct cytosolic translation of truncated proteases or downstream of lysosomal membrane permeabilization. We also discuss the evidence for functions of these proteases upon arrival to the nucleus, including cell cycle progression, cell differentiation, cell death, immune regulation, and epigenetic regulation. As protease substrate profiling methods continue to improve, it is anticipated that many new nuclear substrates and interacting partners will be identified to reveal additional functions for nuclear proteases.

Keywords: Protease; cathepsin; legumain; lysosome; nucleus; proteolysis; trafficking

DOI: https://doi.org/10.1080/10985549.2025.2519158

Nat Cell Biol. 2025 Jun 26.

A lysosomal surveillance response to stress extends healthspan.

Lysosomes are cytoplasmic organelles central for the degradation of macromolecules to maintain cellular homoeostasis and health. However, how lysosomal activity can be boosted to counteract ageing and ageing-related diseases remains elusive. Here we reveal that silencing specific vacuolar H+-ATPase subunits (for example, vha-6), which are essential for intestinal lumen acidification in Caenorhabditis elegans, extends lifespan by ~60%. This longevity phenotype can be explained by an adaptive transcriptional response typified by induction of a set of transcripts involved in lysosomal function and proteolysis, which we termed the lysosomal surveillance response (LySR). LySR activation is characterized by boosted lysosomal activity and enhanced clearance of protein aggregates in worm models of Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis, thereby improving fitness. The GATA transcription factor ELT-2 governs the LySR programme and its associated beneficial effects. Activating the LySR pathway may therefore represent an attractive mechanism to reduce proteotoxicity and, as such, potentially extend healthspan.

DOI: https://doi.org/10.1038/s41556-025-01693-y

J Biol Chem. 2025 Jun 19. pii: S0021-9258(25)02250-1. [Epub ahead of print] 110400

Rag GTPases control lysosomal acidification by regulating v-ATPase assembly in Drosophila.

Ying Zhou, Xiaodie Yang, Wenyu Xu, Sulin Shen, Weikang Fan, Guoqiang Meng, Yang Cheng, Yingying Lu, Youheng Wei.

The Rag GTPases play an important role in sensing amino acids and activating the target of rapamycin complex 1 (TORC1), a master regulator of cell metabolism. Previously, we have shown that GDP-bound RagA stimulates lysosome acidification and autophagic degradation, which are essential for young egg chamber survival under starvation in Drosophila. However, the underlying mechanism is unclear. Here we demonstrate that the GDP-bound RagA breaks the physical interaction between chaperonin containing tailless complex polypeptide 1 (CCT) and Vacuolar H+-ATPase (v-ATPase) subunit V1, and thus promotes the assembly of active v-ATPase and increases the lysosomal acidification. Consistently, knockdown of CCT complex components rescued the accumulation of defective autolysosomes in RagA RNAi. Moreover, the knockdown of Lamtor4, a component of lysosomal adaptor and MAPK and mTOR activator (LAMTOR) that anchors Rag GTPases to the lysosome, resulted in autolysosome accumulation, suggesting that RagGTPases regulate lysosomal acidification depend on their lysosomal localization. Knockdown of the CCT complex components attenuated the autophagic defects in Lamtor 4 RNAi. Our work highlights the interaction between CCT and v-ATPase in regulating lysosomal acidification.

Keywords: Drosophila melanogaster; Rag GTPases; V-ATPase assembly; autophagy; chaperonin containing tailless complex polypeptide 1

DOI: https://doi.org/10.1016/j.jbc.2025.110400

Front Cell Dev Biol. 2025 ;13 1600034

Vesicular trafficking and cell-cell communication in neurodevelopment and neurodegeneration.

Salma Amin, Elena Taverna.

Regulation of vesicle biology and trafficking plays a critical role in cell viability. Vesicular trafficking is a process that entails vesicle biogenesis, transport, and sorting of materials such as proteins, enzymes, hormones, and neurotransmitters to different cellular compartments. This phenomenon is especially important in cells of the central nervous system, including neural progenitors, neurons, and glial cell populations, because of their highly polarized architecture. In line with that, disruption in vesicular trafficking during cortical development affects progenitor proliferation and differentiation and leads to brain malformations. On the other hand, neuronal cells require long-range vesicular trafficking to reach distant locations, such as the distal part of the axons, and synaptic vesicles are essential for cell-cell communication. Neurons have high energy demands. Therefore, any malfunction in vesicular trafficking is a trigger to spiraling into neurodegeneration. Here, we give a comprehensive review of the role of intracellular and extracellular vesicles in cortical development and neurodegeneration, and we discuss how trafficking between organelles in specific cell types contributes to brain pathologies. Finally, we highlight the emerging evidence linking disruption in vesicular trafficking to neurological disorders such as Alzheimer's disease, Parkinson's disease, and autism.

Keywords: brain development; golgi apparatus; lysosomes; neural stem cells; neurons; retrograde and anterograde transport

DOI: https://doi.org/10.3389/fcell.2025.1600034