bims-lypmec 2025-02-16 papers

Immunity. 2025 Feb 11. pii: S1074-7613(25)00037-8. [Epub ahead of print]58(2): 265-267

Next generation lysosome: Brought to you by cGAS-STING.

Renowned for driving interferon responses, the cGAS-STING pathway reveals a surprising role: lysosomal biogenesis. In this issue of Immunity, Xu et al. uncover how STING activates the transcription factor TFEB, linking innate immune sensing to enhanced pathogen clearance through lysosomal activity.

DOI: https://doi.org/10.1016/j.immuni.2025.01.012

Cells. 2025 Jan 24. pii: 183. [Epub ahead of print]14(3):

Lysosome Functions in Atherosclerosis: A Potential Therapeutic Target.

Zhengchao Wang, Xiang Li, Alexandra K Moura, Jenny Z Hu, Yun-Ting Wang, Yang Zhang.

Lysosomes in mammalian cells are recognized as key digestive organelles, containing a variety of hydrolytic enzymes that enable the processing of both endogenous and exogenous substrates. These organelles digest various macromolecules and recycle them through the autophagy-lysosomal system. Recent research has expanded our understanding of lysosomes, identifying them not only as centers of degradation but also as crucial regulators of nutrient sensing, immunity, secretion, and other vital cellular functions. The lysosomal pathway plays a significant role in vascular regulation and is implicated in diseases such as atherosclerosis. During atherosclerotic plaque formation, macrophages initially engulf large quantities of lipoproteins, triggering pathogenic responses that include lysosomal dysfunction, foam cell formation, and subsequent atherosclerosis development. Lysosomal dysfunction, along with the inefficient degradation of apoptotic cells and the accumulation of modified low-density lipoproteins, negatively impacts atherosclerotic lesion progression. Recent studies have highlighted that lysosomal dysfunction contributes critically to atherosclerosis in a cell- and stage-specific manner. In this review, we discuss the mechanisms of lysosomal biogenesis and its regulatory role in atherosclerotic lesions. Based on these lysosomal functions, we propose that targeting lysosomes could offer a novel therapeutic approach for atherosclerosis, shedding light on the connection between lysosomal dysfunction and disease progression while offering new insights into potential anti-atherosclerotic strategies.

Keywords: atherosclerosis; autophagy; endothelial cells; lysosomes; macrophages; smooth muscle cells

DOI: https://doi.org/10.3390/cells14030183

Front Cell Dev Biol. 2025 ;13 1532050

Mechanisms and roles of membrane-anchored ATG8s.

Soo-Kyeong Lee, Sang-Won Park, Deok-Jin Jang, Jin-A Lee.

Autophagy-related protein 8 (ATG8) family proteins, including LC3 and GABARAP subfamilies, are pivotal in canonical autophagy, driving autophagosome formation, cargo selection, and lysosomal fusion. However, recent studies have identified non-canonical roles for lipidated ATG8 in processes such as LC3-associated phagocytosis (LAP), LC3-associated endocytosis (LANDO), and lipidated ATG8-mediated secretory autophagy. These pathways expand ATG8's functional repertoire in immune regulation, membrane repair, and pathogen clearance, as ATG8 becomes conjugated to single-membrane structures (e.g., phagosomes and lysosomes). This review examines the molecular mechanisms of ATG8 lipidation, focusing on its selective conjugation to phosphatidylethanolamine (PE) in autophagy and phosphatidylserine (PS) in CASM. We highlight LIR-based probes and LC3/GABARAP-specific deconjugases as critical tools that allow precise tracking and manipulation of ATG8 in autophagic and non-autophagic contexts. These advancements hold therapeutic promise for treating autophagy-related diseases, including cancer and neurodegenerative disorders, by targeting ATG8-driven pathways that maintain cellular homeostasis.

Keywords: LAP; LC3/GABARAP; LIR motif; Lando; autophagy; deconjugase; non-canonical autophagy; probe

DOI: https://doi.org/10.3389/fcell.2025.1532050

Autophagy. 2025 Feb 12.

Lysosomal Fe2+ influx through the MCOLN1 channel prevents sustained inflammation by limiting PHDs-regulated NFKB activation in macrophages.

Meng-Meng Wang, Wuyang Wang, Jiansong Qi.

Lysosomes are best known for their involvement in inflammatory responses, where they participate in the macroautophagy/autophagy process to eliminate inflammasomes. Recently, we have identified a previously overlooked function of lysosomes in regulating macrophage inflammatory responses. Specifically, lysosomes finely control the production of IL1B (interleukin 1 beta) by manipulating the release of lysosomal Fe2+ through MCOLN1. Mechanistically, reactive oxygen species (ROS), accumulated during sustained inflammation in macrophages, cause activation of the MCOLN1, a lysosomal cationic channel. The activation of MCOLN1 triggers the release of lysosomal Fe2 toward the cytosol, which in turn activates prolyl hydroxylase domain enzymes (PHDs). PHDs' activation represses the transcriptional regulator NFKB/NF-kB (nuclear factor kappa B) activity by restraining RELA/p65 in the cytosol, leading to decreased IL1B transcription in macrophages. Consequently, the property of controlling production and subsequent release of IL1B from macrophages allows the lysosome to finely restrict sustained inflammatory responses. These findings demonstrate that apart from relying on its degradative capability, the lysosome also limits excessive inflammatory responses to facilitate the restoration of cellular and tissue homeostasis in macrophages by modulating the release of lysosomal Fe2+ through MCOLN1. Even more, by suppressing IL1B production, in vivo stimulation of the MCOLN1 channel alleviates multiple clinical symptoms of dextran sulfate sodium (DSS)-induced colitis in mice, highlighting MCOLN1 as a promising therapeutic target for inflammatory bowel disease (IBD) in clinical settings.

Keywords: Lysosomes; MCOLN1; PHDs

DOI: https://doi.org/10.1080/15548627.2025.2465396

J Clin Invest. 2025 Feb 11. pii: e163730. [Epub ahead of print]

Phosphorylation of CRYAB induces a condensatopathy to worsen post-myocardial infarction left ventricular remodeling.

Protein aggregates are emerging therapeutic targets in rare monogenic causes of cardiomyopathy and amyloid heart disease, but their role in more prevalent heart failure syndromes remains mechanistically unexamined. We observed mis-localization of desmin and sarcomeric proteins to aggregates in human myocardium with ischemic cardiomyopathy and in mouse hearts with post-myocardial infarction ventricular remodeling, mimicking findings of autosomal-dominant cardiomyopathy induced by R120G mutation in the cognate chaperone protein, CRYAB. In both syndromes, we demonstrate increased partitioning of CRYAB phosphorylated on serine-59 to NP40-insoluble aggregate-rich biochemical fraction. While CRYAB undergoes phase separation to form condensates, the phospho-mimetic mutation of serine-59 to aspartate (S59D) in CRYAB mimics R120G-CRYAB mutants with reduced condensate fluidity, formation of protein aggregates and increased cell death. Conversely, changing serine to alanine (phosphorylation-deficient mutation) at position 59 (S59A) restored condensate fluidity, and reduced both R120G-CRYAB aggregates and cell death. In mice, S59D CRYAB knock-in was sufficient to induce desmin mis-localization and myocardial protein aggregates, while S59A CRYAB knock-in rescued left ventricular systolic dysfunction post-myocardial infarction and preserved desmin localization with reduced myocardial protein aggregates. 25-Hydroxycholesterol attenuated CRYAB serine-59 phosphorylation and rescued post-myocardial infarction adverse remodeling. Thus, targeting CRYAB phosphorylation-induced condensatopathy is an attractive strategy to counter ischemic cardiomyopathy.

Keywords: Cardiology; Cardiovascular disease; Cell biology; Chaperones

DOI: https://doi.org/10.1172/JCI163730

Diabetes Obes Metab. 2025 Feb 10.

Mechanisms of diabetic cardiomyopathy: Focus on inflammation.

Myriam Bellemare, Liane Bourcier, Josep Iglesies-Grau, Jacinthe Boulet, Eileen O'Meara, Nadia Bouabdallaoui.

PURPOSE OF REVIEW: Type 2 diabetes (T2D) significantly increases the risk of heart failure (HF), either through the progression of coronary artery disease (CAD) or through direct myocardial alterations, termed diabetic cardiomyopathy. This review examines key pathophysiological mechanisms underlying diabetic cardiomyopathy, focusing on the role of inflammation. It also addresses diagnostic and therapeutic approaches to mitigate myocardial damage in T2D.
RECENT FINDINGS: Chronic low-grade inflammation is considered as a major contributor to diabetic cardiomyopathy. T2D-related factors, including hyperglycemia and insulin resistance, activate inflammatory pathways that worsen myocardial dysfunction. Despite advances in understanding these mechanisms, no therapies specifically targeting the cardiac changes in T2D have been identified.
SUMMARY: While significant advances have been made in elucidating the inflammatory mechanisms contributing to diabetic cardiomyopathy, therapeutic advancements remain limited, potentially due to an incomplete understanding of regulatory pathways. A comprehensive investigation into the specific roles of immune cells and inflammatory mediators in diabetic cardiomyopathy is essential for identifying novel therapeutic targets. Expanding our knowledge of these molecular mechanisms has the potential to facilitate the development of innovative therapeutic strategies, thereby improving clinical outcomes in patients with T2D.

Keywords: diabetes; diabetic cardiomyopathy; fibrosis; heart failure; inflammation

DOI: https://doi.org/10.1111/dom.16242