bims-lypmec 2025-02-23 papers

bims-lypmec

Biomed News

on Lysosomal positioning and metabolism in cardiomyocytes

Issue of 2025–02–23
nine papers selected by
Satoru Kobayashi, New York Institute of Technology

Calcium release from damaged lysosomes triggers stress granule formation for cell survival.
Lysosomal Quality Control.
Purifying and profiling lysosomes to expand understanding of lysosomal dysfunction-associated diseases.
LRRK2, lysosome damage, and Parkinson's disease.
Organelle homeostasis requires ESCRTs.
Lysosomal NKG7 restrains mTORC1 activity to promote CD8+ T cell durability and tumor control.
STING-induced noncanonical autophagy regulates endolysosomal homeostasis.
Cardiomyocyte-specific deletion of STING improves cardiac function, glucose homeostasis, and wound healing in diabetic mice.
Rab27b promotes lysosomal function and alpha-synuclein clearance in neurons.

Autophagy. 2025 Feb 17.

Calcium release from damaged lysosomes triggers stress granule formation for cell survival.

Aravinth Kumar Jayabalan, Aanuoluwakiitan Ayeni, Jingyue Jia.

  Lysosomes are essential membrane-bound organelles that integrate intracellular needs and external signals through multiple functions, including autophagy-mediated degradation and MTORC1 signaling. The integrity of the lysosomal membrane is therefore crucial for maintaining cellular homeostasis. Various endogenous and exogenous factors can damage lysosomes, contributing to diseases such as infections, cancer, and neurodegeneration. In response, cells mount defensive mechanisms to cope with such stress, including the formation of stress granules (SGs) - membraneless organelles composed of RNAs and protein complexes. While SGs have emerged as key players in repairing damaged lysosomes, how lysosomal damage triggers their formation and influences cell fate remains unclear. Here we report that the calcium signal from damaged lysosomes mediates SG formation and protects cells from lysosomal damage-induced cell death. Mechanistically, calcium leakage from damaged lysosomes signals the recruitment of calcium-activating protein PDCD6IP/ALIX and its partner PDCD6/ALG2. This complex recruits protein kinase EIF2AK2/PKR and its activator PRKRA/PACT, which phosphorylates translation initiator factor EIF2S1, stalling global translation initiation. This translation arrest leads to the accumulation of inactive messenger ribonucleoprotein complexes (mRNPs), resulting in SG formation. Cells deficient in SG formation show increased cell death when exposed to lysosomal damage from disease-associated factors including SARS-CoV-2ORF3a, adenovirus, malarial pigment, proteopathic MAPT/tau, or environmental hazards. Collectively, this study reveals how damaged lysosomes signal through calcium to trigger SG assembly, promoting cell survival. This establishes a novel link between membrane-bound and membraneless organelles, with implications for diseases involving lysosomal damage and SG dysfunction.

Keywords:  Calcium signaling; cell survival; lysosomal damage; stress granules

DOI:  https://doi.org/10.1080/15548627.2025.2468910
Autophagy. 2025 Feb 19.

Lysosomal Quality Control.

Danielle Henn, Xi Yang, Ming Li.

  Healthy cells need functional lysosomes to degrade cargo delivered by autophagy and endocytosis. Defective lysosomes can lead to severe conditions such as lysosomal storage diseases (LSDs) and neurodegeneration. To maintain lysosome integrity and functionality, cells have evolved multiple quality control pathways corresponding to different types of stress and damage. These can be divided into five levels: regulation, reformation, repair, removal, and replacement. The different levels of lysosome quality control often work together to maintain the integrity of the lysosomal network. This review summarizes the different quality control pathways and discusses the less-studied area of lysosome membrane protein regulation and degradation, highlighting key unanswered questions in the field.

Keywords:  ESCRT; Lysophagy; lysosome membrane protein regulation; lysosome membrane repair; lysosome quality control

DOI:  https://doi.org/10.1080/15548627.2025.2469206
J Clin Invest. 2025 Feb 17. pii: e188507. [Epub ahead of print]135(4):

Purifying and profiling lysosomes to expand understanding of lysosomal dysfunction-associated diseases.

Ali Shilatifard, Issam Ben-Sahra.

Lysosome storage dysfunction plays a central role in numerous human diseases, but a lack of appropriate tools has hindered lysosomal content profiling in clinical settings. In this issue of the JCI, Saarela et al. introduce a method called tagless LysoIP that enabled rapid isolation of intact lysosomes from blood and brain cells via immunoprecipitation of the endogenous protein TMEM192. Applied to the neurodegenerative lysosomal storage disorder known as Batten disease (caused by mutations in the CLN3 gene), tagless LysoIP revealed substantial accumulation of glycerophosphodiesters (GPDs) in patient lysosomes. These findings highlight the role of CLN3 in GPD clearance and present an innovative method that will enable biomarker discovery and therapeutic advancement in lysosomal diseases.

DOI: https://doi.org/10.1172/JCI188507
Curr Opin Cell Biol. 2025 Feb 20. pii: S0955-0674(25)00020-1. [Epub ahead of print]93 102482

LRRK2, lysosome damage, and Parkinson's disease.

Amanda Bentley-DeSousa, Devin Clegg, Shawn M Ferguson.

Limited understanding of regulatory mechanisms controlling LRRK2 kinase activity has hindered insights into both its normal biology and how its dysregulation contributes to Parkinson's disease. Fortunately, recent years have yielded an increased understanding of how LRRK2 kinase activity is dynamically regulated by recruitment to endolysosomal membranes. Notably, multiple small GTPases from the Rab family act as both activators and substrates of LRRK2. Additionally, it was recently discovered that LRRK2 is recruited to, and activated at, stressed or damaged lysosomes through an interaction with GABARAP via the CASM (conjugation of ATG8 to single membranes) pathway. These discoveries position LRRK2 within the rapidly growing field of lysosomal damage and repair mechanisms, offering important insights into lysosome biology and the pathogenesis of Parkinson's disease.

DOI: https://doi.org/10.1016/j.ceb.2025.102482
Curr Opin Cell Biol. 2025 Feb 14. pii: S0955-0674(25)00019-5. [Epub ahead of print]93 102481

Organelle homeostasis requires ESCRTs.

Tsan-Wen Lu, Adam Frost, Frank R Moss.

The endosomal sorting complexes required for transport (ESCRT) catalyze membrane shape transformations throughout the cell. Canonical functions of the ESCRTs include endosomal multivesicular body biogenesis, enveloped virus budding, and abscission of daughter cell plasma membranes. The ESCRT machinery is also required for membranous organelle homeostasis generally, including by facilitating lipid transport at membrane contact sites, repairing membrane damage, driving lysosomal catabolism, and maintaining nuclear envelope integrity, among other roles. Here, we review a subset of recent discoveries and highlight opportunities to better understand how ESCRT activities support cell health.

DOI: https://doi.org/10.1016/j.ceb.2025.102481
Nat Commun. 2025 Feb 14. 16(1): 1628

Lysosomal NKG7 restrains mTORC1 activity to promote CD8+ T cell durability and tumor control.

Hyoungjun Ham, Jacob B Hirdler, Daniel T Bihnam, Zhiming Mao, Joanina K Gicobi, Bruna Gois Macedo, Maria F Rodriguez-Quevedo, Destiny F Schultz, Cristina Correia, Jun Zhong, Kodi E Martinez, Alma Banuelos, Dallin S Ashton, Anthony B Lagnado, Ruifeng Guo, Rodrigo Pessoa, Akhilesh Pandey, Hu Li, Fabrice Lucien, Henrique Borges da Silva, Haidong Dong, Daniel D Billadeau.

During infection and cancer, mTORC1-mediated metabolic regulation impacts CD8+ T cell effector expansion and memory development. However, the mechanisms by which CD8+ T cells regulate mTORC1 to support their unique metabolic requirements remain unknown. Here we show that NKG7, a lysosomal protein whose expression is restricted to cytotoxic lymphocytes, negatively regulates mTORC1 recruitment and activation by inhibiting assembly and function of the lysosomal proton pump, vacuolar ATPase (v-ATPase). Human and mouse CD8+ T cells lacking NKG7 show more acidic lysosomes and increased activation of mTORC1 signaling, which could be reversed by inhibition of v-ATPase activity. In mice responding to LCMV infection, NKG7-deleted effector CD8+ T cells are less durable and generate fewer memory precursors, whereas induced expression of NKG7 in CD8+ T cells results in increased presence of intra-tumoral T cells. Overall, our work identifies NKG7 as a CD8+ T cell-specific regulator of mTORC1 activity, required for optimal immune responses.

DOI: https://doi.org/10.1038/s41467-025-56931-6
Proc Natl Acad Sci U S A. 2025 Feb 25. 122(8): e2415422122

STING-induced noncanonical autophagy regulates endolysosomal homeostasis.

Tuozhi Huang, Chenglong Sun, Fenghe Du, Zhijian J Chen.

  The cGAS-STING pathway mediates innate immune responses to cytosolic DNA. In addition to its well-established role in inducing inflammatory cytokines, activation of the cGAS-STING pathway also induces noncanonical autophagy, a process involving the conjugation of the ATG8 family of ubiquitin-like proteins to membranes of the endolysosomal system. The mechanisms and functions of STING-induced autophagy remain poorly understood. In this study, we demonstrated that STING activation induced formation of pH-elevated Golgi-derived vesicles that led to ATG16L1 and V-ATPase-dependent noncanonical autophagy. We showed that STING-induced noncanonical autophagy resulted in activation of the MiT/TFE family of transcription factors (TFEB, TFE3, and MITF), which regulate lysosome biogenesis. We found that lipidation of the ATG8 proteins, particularly GABARAPs, inhibited phosphorylation of MiT/TFE transcription factors by mTORC1. The lipidated GABARAPs bound to the Folliculin-interacting proteins (FNIPs), thereby sequestering the FNIP-folliculin protein complexes from activating mTORC1, resulting in dephosphorylation and nuclear translocation of MiT/TFE transcription factors. Furthermore, we found that STING-induced autophagy activated Leucine-rich repeat kinase 2 (LRRK2), a protein implicated in Parkinson's disease, through GABARAPs lipidation. We further showed that STING-induced autophagy induced ALIX-mediated ESCRT machinery recruitment to mitigate endolysosomal perturbation. These results reveal the multifaceted functions of STING-induced noncanonical autophagy in regulating endolysosomal homeostasis.

Keywords:  ESCRT; STING; TFEB; autophagy; cGAS

DOI:  https://doi.org/10.1073/pnas.2415422122
Life Sci. 2025 Feb 15. pii: S0024-3205(25)00103-1. [Epub ahead of print]366-367 123470

Cardiomyocyte-specific deletion of STING improves cardiac function, glucose homeostasis, and wound healing in diabetic mice.

Xiaorong Li, Kai Guo, Qingju Zhou, Felycia Fernanda Hosyanto, Guoxiang Zhou, Yiying Zhang, Yuanjing Li, Shenglan Yang.

   AIMS: The present study aimed to investigate the effects and underling mechanisms of cardiomyocyte-specific STING knockout on cardiac function and wound healing in diabetes.
MATERIALS AND METHODS: In this study, type 2 diabetes was induced in cardiomyocyte-specific STING knockout mice using a combination of a high-fat diet and streptozotocin. Cardiac function and remodeling were assessed by echocardiography and histopathological analysis. Glucose homeostasis was evaluated through insulin sensitivity tests and intraperitoneal glucose tolerance tests. Wound healing was quantified by measuring the wound area in diabetic mice.
KEY FINDINGS: The results demonstrated that STING deletion in cardiomyocytes improved cardiac function in diabetic mice, which was accompanied by enhanced insulin sensitivity and improved glucose tolerance. Furthermore, the deletion of STING partially mitigated mitochondrial dysfunction in the myocardium. STING knockout in cardiomyocytes also facilitated angiogenesis and wound healing in diabetic mice.
SIGNIFICANCE: Our findings suggest that cardiomyocyte-specific STING deletion enhances cardiac function, glucose homeostasis, and wound healing, indicating that targeting STING in the heart may serve as a promising therapeutic strategy for managing diabetes mellitus.

Keywords:  Diabetes; Diabetic cardiomyopathy; Glucose homeostasis; Wound healing

DOI:  https://doi.org/10.1016/j.lfs.2025.123470
J Neurosci. 2025 Feb 18. pii: e1579242025. [Epub ahead of print]

Rab27b promotes lysosomal function and alpha-synuclein clearance in neurons.

Kasandra Scholz, Rudradip Pattanayak, Roschongporn Ekkatine, F Sanders Pair, Amber Nobles, William J Stone, Talene A Yacoubian.

Alpha-synuclein (αsyn) is the key pathogenic protein implicated in synucleinopathies including Parkinson's Disease (PD) and Dementia with Lewy Bodies (DLB). In these diseases, αsyn is thought to spread between cells where it accumulates and induces pathology; however, mechanisms that drive its propagation or aggregation are poorly understood. We have previously reported that the small GTPase Rab27b is elevated in human PD and DLB and that it can mediate the autophagic clearance and toxicity of αsyn in a paracrine αsyn cell culture model. Here, we expanded our previous work and characterized a role for Rab27b in neuronal lysosomal processing and αsyn clearance. We found that Rab27b KD in this αsyn inducible neuronal model resulted in lysosomal dysfunction and increased αsyn levels in lysosomes. Similar lysosomal proteolytic defects and enzymatic dysfunction were observed in both primary neuronal cultures and brain lysates from male and female Rab27b knockout (KO) mice. αSyn aggregation was exacerbated in Rab27b KO neurons upon treatment with αsyn preformed fibrils. We found no changes in lysosomal counts or lysosomal pH in either model, but we did identify changes in acidic vesicle trafficking and in lysosomal enzyme maturation and localization, which may drive lysosomal dysfunction and promote αsyn aggregation. Rab27b OE enhanced lysosomal activity and reduced insoluble αsyn accumulation. Finally we found elevated Rab27b levels in human postmortem incidental Lewy Body Disease (iLBD) subjects relative to healthy controls. These data suggest a role for Rab27b in neuronal lysosomal activity and identify it as a potential therapeutic target in synucleinopathies.Significance statement Alpha-synuclein aggregation in Parkinson's disease is associated with autophagic-lysosomal dysfunction, yet the molecular mechanisms underlying alpha-synuclein clearance are not well understood. We identified the small GTPase Rab27b as a novel regulator of the lysosomal clearance of alpha-synuclein. Using several alpha-synuclein models, we found that Rab27b knockdown or knockout impairs lysosomal function, increases alpha-synuclein lysosomal accumulation, and increases alpha-synuclein aggregation. Conversely, Rab27b overexpression promotes lysosomal function and reduces alpha-synuclein aggregation. We also identified defects in lysosomal enzyme maturation and localization and acidic vesicle trafficking upon Rab27b loss, which may drive lysosomal dysfunction. These findings suggest that targeting Rab27b could boost lysosomal clearance of alpha-synuclein in synucleinopathies.

DOI: https://doi.org/10.1523/JNEUROSCI.1579-24.2025