bims-lycede 2025-04-13 papers

bims-lycede

Biomed News

on Lysosome-dependent cell death

Issue of 2025–04–13
six papers selected by
Sofía Peralta, Universidad Nacional de Cuyo

STING mediates lysosomal quality control and recovery through its proton channel function and TFEB activation in lysosomal storage disorders.
Steroid signaling in autophagy.
Lysosomes: guardians and healers within cells- multifaceted perspective and outlook from injury repair to disease treatment.
The autophagy protein ATG-9 regulates lysosome function and integrity.
mTORC1 shutdown unleashes TFEB to drive triple-negative breast cancer invasion.
Rab GTPases are evolutionarily conserved signals mediating selective autophagy.

Mol Cell. 2025 Mar 27. pii: S1097-2765(25)00201-1. [Epub ahead of print]

STING mediates lysosomal quality control and recovery through its proton channel function and TFEB activation in lysosomal storage disorders.

Zhen Tang, Cong Xing, Antonina Araszkiewicz, Kun Yang, Wanwan Huai, Devon Jeltema, Nicole Dobbs, Yihe Zhang, Lu O Sun, Nan Yan.

  Lysosomes are essential organelles for cellular homeostasis. Defective lysosomes are associated with diseases like lysosomal storage disorders (LSDs). How lysosomal defects are detected and lysosomal function restored remain incompletely understood. Here, we show that STING mediates a neuroinflammatory gene signature in three distinct LSD mouse models, Galctwi/twi, Ppt1-/-, and Cln7-/-. Transcriptomic analysis of Galctwi/twi mouse brain tissue revealed that STING also mediates the expression of lysosomal genes that are regulated by transcriptional factor EB (TFEB). Immunohistochemical and single-nucleus RNA-sequencing (snRNA-seq) analysis show that STING regulates lysosomal gene expression in microglia. Mechanistically, we show that STING activation leads to TFEB dephosphorylation, nuclear translocation, and expression of lysosomal genes. This process requires STING's proton channel function, the V-ATPase-ATG5-ATG8 cascade, and is independent of immune signaling. Furthermore, we show that the STING-TFEB axis facilitates lysosomal repair. Together, our data identify STING-TFEB as a lysosomal quality control mechanism that responds to lysosomal dysfunction.

Keywords:  Krabbe disease; Niemann-Pick disease; STING; TFEB; innate immunity; lysosomal storage disorder; lysosome repair; neuroinflammation; non-canonical autophagy

DOI:  https://doi.org/10.1016/j.molcel.2025.03.008
J Mol Biol. 2025 Apr 08. pii: S0022-2836(25)00200-1. [Epub ahead of print] 169134

Steroid signaling in autophagy.

Ivan Bradic, Kim Rewitz.

Autophagy is a conserved cellular process essential for homeostasis and development that plays a central role in the degradation and recycling of cellular components. Recent studies reveal bidirectional interactions between autophagy and steroid-hormone signaling. Steroids are signaling molecules synthesized from cholesterol that regulate key physiological and developmental processes - including autophagic activity. Conversely, other work demonstrates that autophagy regulates steroid production by controlling the availability of precursor sterol substrate. Insights from Drosophila and mammalian models provide compelling evidence for the conservation of these mechanisms across species. In this review we explore how steroid hormones modulate autophagy in diverse tissues and contexts, such as metabolism and disease, and discuss advances in our understanding of autophagy's regulatory role in steroid hormone production. We examine the implications of these interactions for health and disease and offer perspectives on the potential for harnessing this functionality for addressing cholesterol-related disorders.

DOI: https://doi.org/10.1016/j.jmb.2025.169134
Cancer Cell Int. 2025 Apr 09. 25(1): 136

Lysosomes: guardians and healers within cells- multifaceted perspective and outlook from injury repair to disease treatment.

Jianlei Bi, Yincong Sun, Meihua Guo, Xiaoxin Sun, Jie Sun, Rujiao Jiang, Ning Wang, Gena Huang.

Lysosomes, as crucial organelles within cells, carry out diverse biological functions such as waste degradation, regulation of the cellular environment, and precise control of cell signaling. This paper reviews the core functions and structural characteristics of lysosomes, and delves into the current research status of lysosomes damage repair mechanisms. Subsequently, we explore in depth the close association between lysosomes and various diseases, including but not limited to age-related chronic diseases, neuro-degenerative diseases, tumors, inflammation, and immune imbalance. Additionally, we also provide a detailed discussion of the application of lysosome-targeted substances in the field of regenerative medicine, especially the enormous potential demonstrated in key areas such as stem cell regulation and therapy, and myocardial cell repair. Though the integration of multidisciplinary research efforts, we believe that lysosomes damage repair mechanisms will demonstrate even greater application value in disease treatment and regenerative medicine.

DOI: https://doi.org/10.1186/s12935-025-03771-5
J Cell Biol. 2025 Jun 02. pii: e202411092. [Epub ahead of print]224(6):

The autophagy protein ATG-9 regulates lysosome function and integrity.

Kangfu Peng, Guoxiu Zhao, Hongyu Zhao, Nobuo N Noda, Hong Zhang.

The transmembrane autophagy protein ATG9 has multiple functions essential for autophagosome formation. Here, we uncovered a novel function of ATG-9 in regulating lysosome biogenesis and integrity in Caenorhabditis elegans. Through a genetic screen, we identified that mutations attenuating the lipid scrambling activity of ATG-9 suppress the autophagy defect in epg-5 mutants, in which non-degradative autolysosomes accumulate. The scramblase-attenuated ATG-9 mutants promote lysosome biogenesis and delivery of lysosome-localized hydrolases and also facilitate the maintenance of lysosome integrity. Through manipulation of phospholipid levels, we found that a reduction in phosphatidylethanolamine (PE) also suppresses the autophagy defects and lysosome damage associated with impaired lysosomal degradation. Our results reveal that modulation of phospholipid composition and distribution, e.g., by attenuating the scramblase activity of ATG-9 or reducing the PE level, regulates lysosome function and integrity.

DOI: https://doi.org/10.1083/jcb.202411092
Dev Cell. 2025 Apr 07. pii: S1534-5807(25)00153-4. [Epub ahead of print]60(7): 979-981

mTORC1 shutdown unleashes TFEB to drive triple-negative breast cancer invasion.

Michalis Gounis, Hellyeh Hamidi, Johanna Ivaska.

The PI3K/AKT/mTOR pathway is considered a key therapeutic target in triple-negative breast cancer (TNBC). In this issue of Developmental Cell, Remy et al. challenge this idea by demonstrating that mTORC1 inhibition activates TFEB, promoting MT1-MMP exocytosis, ECM degradation, and increased cell invasion, especially when combined with chemotherapy.

DOI: https://doi.org/10.1016/j.devcel.2025.03.006
J Cell Biol. 2025 May 05. pii: e202410150. [Epub ahead of print]224(5):

Rab GTPases are evolutionarily conserved signals mediating selective autophagy.

Pengwei Zhao, Rui Tian, Dandan Song, Qi Zhu, Xianming Ding, Jianqin Zhang, Beibei Cao, Mengyuan Zhang, Yilu Xu, Jie Fang, Jieqiong Tan, Cong Yi, Hongguang Xia, Wei Liu, Wei Zou, Qiming Sun.

Selective autophagy plays a crucial role in maintaining cellular homeostasis by specifically targeting unwanted cargo labeled with "autophagy cues" signals for autophagic degradation. In this study, we identify Rab GTPases as a class of such autophagy cues signals involved in selective autophagy. Through biochemical and imaging screens, we reveal that human Rab GTPases are common autophagy substrates. Importantly, we confirm the conservation of Rab GTPase autophagic degradation in different model organisms. Rab GTPases translocate to damaged mitochondria, lipid droplets, and invading Salmonella-containing vacuoles (SCVs) to serve as degradation signals. Furthermore, they facilitate mitophagy, lipophagy, and xenophagy, respectively, by recruiting receptors. This interplay between Rab GTPases and receptors may ensure the de novo synthesis of isolation membranes around Rab-GTPase-labeled cargo, thereby mediating selective autophagy. These processes are further influenced by upstream regulators such as LRRK2, GDIs, and RabGGTase. In conclusion, this study unveils a conserved mechanism involving Rab GTPases as autophagy cues signals and proposes a model for the spatiotemporal control of selective autophagy.

DOI: https://doi.org/10.1083/jcb.202410150