bims-lycede 2025-02-16 papers

Autophagy. 2025 Feb 12.

Transcriptional repression of autophagy and lysosome biogenesis.

Jaebeom Kim, Young Suk Yu, Keun Il Kim, Sung Hee Baek.

The microphthalmia/transcription factor E (MiT/TFE) family activates macroautophagy/autophagy and lysosomal genes during acute nutrient deficiency. However, the mechanisms that suppress transcription of these genes under steady-state, nutrient-rich conditions to prevent unnecessary expression remain unclear. In this study, we identified a previously unrecognized mechanism of transcriptional repression for autophagy and lysosomal genes. Under nutrient-rich conditions, USF2 (upstream transcription factor 2) binds to the coordinated lysosomal expression and regulation (CLEAR) motif, recruiting a repressive complex containing HDAC (histone deacetylase). In contrast, during nutrient deficiency, TFEB (transcription factor EB) displaces USF2 at the same motif, activating transcription. This switch is regulated by USF2 phosphorylation at serine 155 by GSK3B (glycogen synthase kinase 3 beta). Reduced phosphorylation under nutrient-deprived conditions weakens USF2's DNA binding affinity, allowing TFEB to competitively bind and activate target genes. Knockdown or knockout of Usf2 upregulates specific autophagy and lysosomal genes, leading to enhanced lysosomal functionality and increased autophagic flux. In USF2-deficient cells, the SERPINA1 Z variant/antitrypsin Z - an aggregation-prone mutant protein used as a model - is rapidly cleared via the autophagy-lysosome pathway. Therefore, modulation of USF2 activity may be a therapeutic strategy for managing diseases associated with autophagy and lysosomal dysfunction.

Keywords: Autophagy; MiT/TFE; TFEB; USF2; lysosome; transcriptional repressor

DOI: https://doi.org/10.1080/15548627.2025.2465404

Sci Rep. 2025 Feb 12. 15(1): 5148

Bafilomycin A1 induces colon cancer cell death through impairment of the endolysosome system dependent on iron.

Dong Hwa Min, Dasom Kim, Seung Taek Hong, Joohee Kim, Min Jung Kim, Seung-Hae Kwon, Aeree Kim, Ji-Yun Lee.

The late endolysosomal compartment plays a crucial role in cancer cell metabolism by regulating lysosomal activity, essential for cell proliferation, and the degradation of cellular components during the final stages of autophagy. Modulating late endolysosomal function represents a new target for cancer therapy. In this study, we investigated the effects of bafilomycin A1 (BA1), a vacuolar H+-ATPase inhibitor, on colon cancer and normal colon fibroblasts (CCD-18Co) cells. We found that very low concentrations (~ 2 nM) of BA1 selectively induced cell death in colon cancer cells. This cytotoxicity was associated with lysosomal stress response and dysregulation of iron homeostasis. BA1 treatment resulted in significant alterations to the endolysosomal system, including an increased number and size of lysosomes, lysosomal membrane permeabilization, and autophagy flux blockade. These changes were accompanied by endoplasmic reticulum stress and lipid droplet accumulation. Furthermore, BA1 decreased intracellular Fe2+ levels, as measured using FerroOrange. Notably, iron (III)-citrate supplementation rescued cells from BA1-induced death. These findings suggest that BA1-induced endolysosomal dysfunction impairs iron homeostasis, ultimately leading to colon cancer cell death. Our results highlight the potential of targeting endolysosomal function and iron homeostasis as novel therapeutic strategies for colon cancer, paving the way for more selective and effective treatments.

Keywords: Autophagy; Bafilomycin A1; Colorectal cancer; Endolysosome; Iron

DOI: https://doi.org/10.1038/s41598-025-89127-5

Cell Rep. 2025 Feb 12. pii: S2211-1247(25)00053-1. [Epub ahead of print]44(2): 115282

Selective clearance of aberrant membrane proteins by TORC1-mediated micro-ER-phagy.

Valeriya Gyurkovska, Yaneris M Alvarado Cartagena, Rakhilya Murtazina, Sarah F Zhao, Candela Ximenez de Olaso, Nava Segev.

Aberrant accumulation and clearance of membrane proteins is associated with disease. Membrane proteins are inserted first to the endoplasmic reticulum (ER). During normal growth, two quality control (QC) processes, ER-associated degradation and macro-ER-phagy, deliver misfolded and excess membrane proteins for degradation in the proteasome and lysosome, respectively. We show that in yeast during normal growth, ER-QC is constitutive, since none of the stress-induced signaling pathways-nutritional, proteotoxic, or heat-are involved. In mutant cells defective in ER-QC, misfolded or excess proteins accumulate and nutritional stress, but not proteotoxic or heat stress, can stimulate their clearance. Early during nutritional stress, clearance occurs in the lysosome through a selective micro-ER-phagy pathway dependent on the ubiquitin ligase Rsp5, its Ssh4 adaptor, and ESCRT. In contrast, only a fraction of normal membrane proteins is degraded much later via macro-autophagy. Because the pathways explored here are conserved, nutritional stress emerges as a possible way for clearing disease-associated membrane proteins.

Keywords: CP: Cell biology; ER-quality control; ERAD; Endoplasmic reticulum; HSR; TORC1; UPR; macro-ER-phagy; micro-ER-phagy; nutritional stress

DOI: https://doi.org/10.1016/j.celrep.2025.115282