bims-lycede 2025-01-26 papers

Autophagy. 2025 Jan 21.

Induction of lysosome biogenesis is a novel function of the CGAS-STING1 pathway.

Induction of macroautophagy/autophagy has been established as an important function elicited by the CGAS-STING1 pathway during pathogen infection. However, it remains unknown whether lysosomal activity within the cell in these settings is concurrently enhanced to cope with the increased autophagic flux. Recently, we discovered that the CGAS-STING1 pathway elevates the degradative capacity of the cell by activating lysosome biogenesis. Intriguingly, we found that STING1-induced GABARAP lipidation, rather than TBK1 activation, serves as the key mediator triggering the nuclear translocation of transcription factor TFEB and enhances the expression of lysosome-related genes. Mechanistically, we demonstrated that lipidated GABARAP on single membranes, regulated by the V-ATPase-ATG16L1 axis, sequesters the FLCN-FNIP complex to abolish its function toward RRAGC-RRAGD, leading to a specific impairment of MTORC1-dependent phosphorylation of TFEB and resulting in its subsequent nuclear translocation. Functionally, we showed that STING1-induced lysosome biogenesis is essential for the clearance of cytoplasmic DNA and the elimination of invading pathogens. Collectively, our findings underscore the induction of lysosome biogenesis as a novel function of the CGAS-STING1 pathway.China; Yinfeng Xu; Email: yinfengxu@hnfnu.edu.cn; Hunan First Normal University, 1015 Feng-Lin-San Road, Changsha, Hunan 410,205, China.

Keywords: Autophagy; CGAS; GABARAP; STING1; TFEB; lysosome

DOI: https://doi.org/10.1080/15548627.2025.2456064

Br J Pharmacol. 2025 Jan 21.

Cathepsins: Novel opportunities for antibody therapeutics in cancer.

Timothée David, Pénélope Desroys du Roure, Aude Mallavialle, Valérie Laurent-Matha, Pascal Roger, Séverine Guiu, Thierry Chardès, Emmanuelle Liaudet-Coopman.

Cathepsins, the most abundant lysosomal proteases, have key functions in cell maintenance and homeostasis. They are overexpressed and hypersecreted in cancer and associated with poor prognosis. Secreted cathepsins display pro-tumour activities in the tumour microenvironment and thus represent interesting molecular targets in oncology. Recently, several antibody-based cancer therapies have targeted the pro-tumour activity of the extracellular cathepsin pool, altering several cancer hallmarks, but not the intracellular cathepsin levels that are often crucial for cell homeostasis. In this mini-review, we describe advances in antibodies against extracellular cathepsins in cancer, and their effect on the proteolytic cascade, matrix remodelling, proliferation, and modulation of the anti-cancer immune response. We also discuss the add-on value of combination strategies (anti-cathepsin antibodies with chemotherapy and/or biologics) that make anti-cathepsin antibodies a new opportunity for disease management.

Keywords: ECM; antibody‐based therapy; biologics; cathepsins; cell signalling; chemotherapeutic drugs; immunomodulation; proteolysis; tumour microenvironment

DOI: https://doi.org/10.1111/bph.17437

Discov Oncol. 2025 Jan 22. 16(1): 76

A Golgi apparatus‑related subtype and risk signature predicts prognosis and evaluates immunotherapy response in gastric cancer.

Ruyue Chen, Zengwu Yao, Lixin Jiang, Jinchen Hu.

BACKGROUND: Gastric cancer (GC) remains a significant health burden, calling for the discovery of novel biomarkers. Golgi apparatus, a crucial cellular organelle involved in tumorigenesis, remains underexplored in GC research. A comprehensive understanding of its role and associated mechanisms is urgently needed.
MATERIALS AND METHODS: Utilizing the TCGA-STAD dataset as the training cohort and GSE84433 as the validation cohort, we explored potential associations between Golgi apparatus-related genes (GARG) and GC clinical risk. We aimed to decipher the prognostic significance and underlying biological mechanisms of these genes via consistent clustering, differential expression analysis, enrichment analyses, and immune infiltration profiling. To assess the relationship between risk stratification and survival outcomes, drug sensitivity, and immune infiltration, we developed the Golgi Apparatus-Related Risk Signature (GARRS). The reliability of GARRS was further corroborated using immunohistochemical staining.
RESULTS: Consensus clustering based on 17 GARG identified two patient subgroups, C1 and C2, exhibiting differential survival, immune scores, and immune cell infiltration. We developed a GARRS using Cox-Lasso regression analysis, accurately stratifying patients into high- and low-risk groups. GARRS' validity was confirmed in the validation set and immunohistochemical staining. Our findings underline the Golgi apparatus' significance in the GC immune microenvironment and GARRS' utility in predicting GC survival outcomes.
CONCLUSION: This study underscores the association between Golgi apparatus subtypes and GC immunotumor microenvironment. GARRS, validated for its prognostic, immune infiltration, and drug sensitivity predictive abilities, offers new insights into gastric cancer treatment strategies.

Keywords: Gastric cancer; Golgi apparatus; Immunotherapy; Prognosis; Subtype

DOI: https://doi.org/10.1007/s12672-025-01827-6

Front Cell Dev Biol. 2024 ;12 1513472

The role of Golgi complex proteins in cell division and consequences of their dysregulation.

Roberta Iannitti, Fabiola Mascanzoni, Antonino Colanzi, Daniela Spano.

The GC (Golgi complex) plays a pivotal role in the trafficking and sorting of proteins and lipids until they reach their final destination. Additionally, the GC acts as a signalling hub to regulate a multitude of cellular processes, including cell polarity, motility, apoptosis, DNA repair and cell division. In light of these crucial roles, the GC has garnered increasing attention, particularly given the evidence that a dysregulation of GC-regulated signalling pathways may contribute to the onset of various pathological conditions. This review examines the functions of the GC and GC-localised proteins in regulating cell cycle progression, in both mitosis and meiosis. It reviews the involvement of GC-resident proteins in the formation and orientation of the spindle during cell division. In light of the roles played by the GC in controlling cell division, this review also addresses the involvement of the GC in cancer development. Furthermore, TCGA (The Cancer Genome Atlas) database has been queried in order to retrieve information on the genetic alterations and the correlation between the expression of GC-localised proteins and the survival of cancer patients. The data presented in this review highlight the relevance of the GC in regulating cell cycle progression, cellular differentiation and tumourigenesis.

Keywords: Golgi complex; cancer; cell fate; meiosis; mitosis

DOI: https://doi.org/10.3389/fcell.2024.1513472