bims-raghud 2025-12-28 papers

Issue of 2025–12–28
three papers selected by
Irene Sambri, TIGEM

Autophagy. 2025 Dec 26.

Proteotoxic stress triggers TFEB- and TFE3-mediated autophagy and lysosomal biogenesis via non-canonical MTORC1 inactivation.

Zhou Zhu, Jing Yang, Sandro Montefusco, Siyu Xia, Jinhuan Ou, Haibo Tong, Qingzhong Zeng, Fengmei Xu, Lingyun Dai, Jichao Sun, Chengchao Xu, Diego Luis Medina, Jigang Wang, Wei Zhang, Chuanbin Yang.

Proteotoxic stress, arising from conditions that cause misfolded protein accumulation, is closely linked to the pathogenesis of multiple diseases. Macroautophagy/autophagy activation is considered a compensatory mechanism to maintain protein homeostasis, but the underlying regulatory mechanisms remain incompletely understood. Here, we show that proteotoxic stress induced by proteasome inhibition, puromycin treatment, or polyglutamine-expanded HTT (huntingtin) expression promotes nuclear accumulation of TFEB and TFE3, key regulators of lysosomal biogenesis and autophagy. Mechanistically, TFEB activation under proteotoxic stress occurs independently of canonical MTORC1 inactivation mediated by TSC2 or ATF4. Instead, it involves non-canonical inhibition of MTORC1 via RRAG GTPases. Proteotoxic stress disrupts the RRAGC-TFEB interaction, preventing TFEB recruitment to lysosomes and subsequent MTORC1 phosphorylation. An activated RRAGC mutant rescues impaired lysosomal localization and nuclear accumulation of TFEB, while co-overexpression of FLCN and FNIP2, a GAP for RRAGC, partially restores stress-induced TFEB dephosphorylation. In addition, proteasome inhibition activates non-canonical autophagy. Deletion of ATG16L1 or ATG5, which blocks Atg8-familyh protein lipidation and sequesters the FLCN-FNIP2 complex, partially abolishes proteotoxic stress-induced TFEB dephosphorylation and nuclear accumulation. Together, these findings demonstrate that proteotoxic stress triggers both non-canonical autophagy and TFEB-mediated canonical autophagy, with Atg8-family protein lipidation contributing to TFEB activation. Our results provide novel insights into how proteotoxic stress engages non-canonical MTORC1 inhibition and TFEB activation, thereby enhancing understanding of cellular adaptation to proteotoxic stress.

Keywords: Autophagy; MTORC1; RRAG GTPase; TFEB; lysosomal biogenesis; proteosome

DOI: https://doi.org/10.1080/15548627.2025.2608973

J Pers Med. 2025 Dec 01. pii: 583. [Epub ahead of print]15(12):

Birt-Hogg-Dubé Syndrome: A Mini Review of the Clinical Manifestations, Investigation, and Management.

Christina Ntinidi, Ioannis Tomos, Andreas M Matthaiou, Nikoleta Bizymi, Adamantia Liapikou.

Birt-Hogg-Dubé (BHD) syndrome is a rare genetic disease, inherited in an autosomal dominant manner, that was first described in the mid-1970s and occurs due to pathogenic variants in the folliculin gene (FLCN) on chromosome 17p11.2. The syndrome has numerous clinical manifestations and primarily affects the lungs, kidneys, and skin. As far as the pulmonary features are concerned, more than 80% of patients appear to develop bilateral pulmonary cysts located in the lower lung zones, in the subpleural area, with cumulative risk of spontaneous pneumothorax depending on the number of cysts in the lungs. Another serious feature of the syndrome is the increased risk of renal cell carcinoma, which is often an incidental finding on screening or medical imaging. Cutaneous manifestations include benign fibrofolliculomas, trichodiscomas, and acrochordons (skin tags), which primarily affect the patients' emotional status as a result of their cosmetic defects. BHD syndrome is generally an underdiagnosed condition due to the great variability of its clinical picture, thus highlighting the importance of genetic testing for FLCN mutations in suspected cases. The application of ERN GENTURIS guidelines in clinical practice can facilitate early, accurate diagnosis of the disease and optimal personalized management of the patients.

Keywords: Birt–Hogg–Dubé syndrome; cystic lung disease; genetic disease; rare disease

DOI: https://doi.org/10.3390/jpm15120583

bioRxiv. 2025 Dec 16. pii: 2025.12.13.693777. [Epub ahead of print]

Dapagliflozin mitigates hypoxia-induced metabolic stress, kidney tubular cell death and fibrosis.

Sodium-glucose co-transporter 2 inhibitors (SGLT2-i) slow progression of kidney disease but therapeutic mechanisms remain elusive. Here we report the beneficial effect of dapagliflozin on hypoxia-mediated kidney tubular epithelial cell injury, a contributing factor to kidney disease progression, using a human pluripotent stem cell (hPSC)-derived hypoxic kidney organoid model. Hypoxic organoids showed increased expression of Hypoxia Inducible Factor (HIF)-associated transcriptional targets, decreased tricarboxylic acid (TCA) cycle metabolites and mitochondrial β-oxidation protein expression, and activated unfolded protein response. A transcriptional signature derived from hypoxic organoids 1) identified a subgroup of individuals whose kidney disease subsequently progressed, and 2) correlated with worse tubular injury. Dapagliflozin enhanced mitochondrial stress response resulting in reversed hypoxia-induced tubular epithelial cell apoptosis, reactive oxygen species (ROS) accumulation, and organoid fibrosis. These results indicate that dapagliflozin may contribute to improved kidney disease outcomes by attenuating hypoxia-induced metabolic stress-mediated tubular epithelial cell injury.

DOI: https://doi.org/10.64898/2025.12.13.693777