EPHA2 and scavenger receptor-directed trafficking enhances endosomal leakiness and antisense therapy delivery

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 6, 2025

Summary The potential for using therapeutic antisense oligonucleotides (ASOs) has been hampered by lack of understanding how they enter cells and subsequently access their targets. Endocytosis contributes to ASO uptake, but the machinery mediating subsequent trafficking permit suppression target mRNAs not described. Here, we show that engagement with a scavenger receptor (CD44) activates ERK-RSK axis promote serine phosphorylation tyrosine kinase (EPHA2). Serine EPHA2 permits endocytosis, trafficking, accumulation ASOs in nuclear-adjacent endosomes. These endosomes then become leaky, allowing escape effectively suppress mRNA expression. Inhibition stress granule-mediated repair leaky further enhances effectiveness. data identify an endocytic route nucleus which may be exploited maximise effectiveness ASO-mediated therapies.

Language: Английский

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Pathways to Repair or Remove Lysosomes Damaged by Extracellular Fine Particles

Published: Jan. 1, 2025

Abstract Exogenous and endogenous fine particles such as environmental materials (e.g., silica, asbestos, alum), toxic protein aggregates α-synuclein, amyloid-β), crystals cholesterol crystals, uric acid crystals) are internalized into the cell by endocytic pathway or phagocytosis. Because lysosomes terminal compartments of these pathways, known to be damaged exocytosed extracellular particles. Lysosomal membrane damage allows leakage lysosomal contents cathepsins, H + , Ca 2+ iron cytosol, which is harmful cell. Numerous studies have suggested that tightly associated with toxicity exogenous particles, inflammatory responses, diseases including those involving neurodegeneration. To preserve integrity, cells several mechanisms for repair elimination compromised collectively called “lysosomal response”. This review summarizes recent findings on responses damage, focusing

Language: Английский

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Lysosomes’ fallback strategies: more than just survival or death

Frontiers in Cell and Developmental Biology, Journal Year: 2025, Volume and Issue: 13

Published: March 11, 2025

Lysosomes are heterogeneous, acidic organelles whose proper functionality is critically dependent on maintaining the integrity of their membranes and acidity within lumen. When subjected to stress, lysosomal membrane can become permeabilized, posing a significant risk organelle’s survival necessitating prompt repair. Although numerous mechanisms for repair have been identified in recent years, progression lysosome-related diseases more closely linked alternative strategies when fail, particularly contexts aging pathogen infection. This review explores responses damage, including secretion contents interactions with lysosome-associated endolysosomal system. Furthermore, it examines role outside this system, such as endoplasmic reticulum (ER) Golgi apparatus, auxiliary These crucial understanding disease progression. For instance, spread misfolded proteins play key roles neurodegenerative advancement, while escape via lysosomotropic drug expulsion underlie cancer treatment resistance. Reexamining these fallback could provide new perspectives biology contribution

Language: Английский

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ATXN2L primarily interacts with NUFIP2, the absence of ATXN2L results in NUFIP2 depletion, and the ATXN2-polyQ expansion triggers NUFIP2 accumulation

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 11, 2025

Abstract The cytoplasmic Ataxin-2 (ATXN2) protein associates with TDP-43 in stress granules (SG) where RNA quality control occurs. Mutations this pathway underlie Spinocerebellar Ataxia type 2 (SCA2) and Amyotrophic Lateral Sclerosis. In contrast, Ataxin-2-like (ATXN2L) is predominantly nuclear, more abundant, essential for embryonic life. Its sequestration into ATXN2 aggregates may contribute to disease. study, we utilized two approaches clarify the roles of ATXN2L. First, identified interactors through co-immunoprecipitation both wild-type ATXN2L-null murine fibroblasts. Second, assessed proteome profile effects using mass spectrometry these cells. Additionally, examined accumulation ATXN2L SCA2 mouse model, Atxn2-CAG100-KnockIn (KIN). We observed that RNA-binding proteins, including PABPN1, NUFIP2, MCRIP2, RBMS1, LARP1, PTBP1, FMR1, RPS20, FUBP3, MBNL2, ZMAT3, SFPQ, CSDE1, HNRNPK, HNRNPDL, exhibit a stronger association compared established like ATXN2, PABPC1, LSM12, G3BP2. interacted components actin complex, such as SYNE2, LMOD1, ACTA2, FYB, GOLGA3. noted oxidative increased HNRNPK but decreased SYNE2 association, which likely reflects relocalization SG. Proteome profiling revealed NUFIP2 are depleted Furthermore, homodimers SYNE1 accumulate during aggregation process KIN 14-month-old spinal cord tissues. functions its therefore critical granule trafficking surveillance, particularly maintenance differentiated neurons.

Language: Английский

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Action and therapeutic targets of folliculin interacting protein 1: a novel signaling mechanism in redox regulation

Frontiers in Cell and Developmental Biology, Journal Year: 2025, Volume and Issue: 13

Published: March 12, 2025

Rapid activation of adenosine monophosphate-activated protein kinase (AMPK) induces phosphorylation mitochondrial-associated proteins, a process by which phosphate groups are added to regulate mitochondrial function, thereby modulating energy metabolism, triggering an acute metabolic response, and sustaining adaptation through transcriptional regulation. AMPK directly phosphorylates folliculin interacting 1 (FNIP1), leading the nuclear translocation transcription factor EB (TFEB) in response functions. While function is tightly linked finely-tuned energy-sensing mobility, FNIP1 plays critical roles glucose transport sensing, autophagy, cellular stress muscle fiber contraction. Consequently, emerges as promising novel target for addressing aberrant metabolism. Recent evidence indicates that implicated biology various pathways, including AMPK, mTOR, ubiquitination, oxidative responses, skeletal Nonetheless, there dearth literature discussing physiological mechanism action therapeutic target. This review outlines how regulates metabolic-related signaling pathways enzyme activities, such catalytic activity enzymes, homeostasis products, controlling fate different contexts. Our focus will be on elucidating these metabolite-mediated processes inflammatory diseases.

Language: Английский

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