bims-raghud 2026-02-22 papers

Issue of 2026–02–22
five papers selected by
Irene Sambri, TIGEM

J Clin Invest. 2026 Feb 16. pii: e194300. [Epub ahead of print]136(4):

Hyperactivation of mTORC1 signaling mediates folliculin deficiency-induced pulmonary cyst formation in Birt-Hogg-Dubé syndrome.

Ke Cao, Hui Chen, Ling Chu, Hong-Jun Wang, Jianhua Zhang, Yongfeng Luo, Joanne Chiu, Damir Khabibullin, Nicola Alesi, Matthew E Thornton, Brendan H Grubbs, Ali Ataya, Nishant Gupta, Francis X McCormack, Kathryn A Wikenheiser-Brokamp, Elizabeth P Henske, Wei Shi.

Germline loss-of-function folliculin (FLCN) gene mutations cause Birt-Hogg-Dubé (BHD) syndrome, in which pulmonary cysts are present in up to 90% of the patients. The pathogenic mechanisms underlying lung cyst development in BHD are almost entirely unknown because of the limited availability of BHD patient lung samples and the lack of authentic BHD lung disease models. We generated lung mesenchyme-specific and lung epithelium-specific Flcn-knockout mice using a Cre/loxP approach. We found that deletion of Flcn in lung mesenchymal cells, but not in lung epithelial cells, resulted in alveolar enlargement starting from early postnatal life, with evidence of cyst formation in adult mice, resembling the pulmonary disease in human BHD. These changes were associated with increased mechanistic target of rapamycin complex 1 (mTORC1) activity in the lungs of both patients with BHD and Flcn-knockout mice. Attenuation of mTORC1 activity by knocking out Raptor gene (Rptor) or pharmacologic inhibition using rapamycin substantially rescued the pulmonary pathology caused by Flcn deletion in mice. Taken together, these human and mouse data support a model in which mTORC1 hyperactivation drives pulmonary cystic pathology in BHD.

Keywords: Cell biology; Development; Mouse models; Pulmonology; Tumor suppressors

DOI: https://doi.org/10.1172/JCI194300

Mol Genet Genomic Med. 2026 Mar;14(3): e70205

Severe Renal Phenotype Across A Multigenerational Tuberous Sclerosis Complex (TSC) Family.

Elena Tuller, Joshua A Samuels, Hope Northrup, Kate Richardson.

BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized by the formation of hamartomas in the brain, kidney, and heart, along with other complex clinical manifestations, including TSC-associated neuropsychiatric disorder (TAND). Development of genotype-phenotype correlations within TSC can aid clinicians in providing prognostic data and improve clinical management. We present here a multigenerational family who has a pathogenic variant in TSC2 displaying a severe renal phenotype.
METHODS: A 23-year-old Caucasian male (Patient 1) was determined to have a molecularly confirmed diagnosis of TSC at approximately 2 months of age. The nonsense pathogenic variant (c.1372C>T (p.Arg458*)) in TSC2 had been previously identified in his father (Patient 6), grandmother (Patient 5), and other extended paternal family members (Patient 2, 3, 4, 7).
RESULTS: Clinical evaluations revealed that the affected family members display a severe renal phenotype characterized by large angiomyolipoma burden (AMLs), renal cystic disease, and chronic kidney disease leading to renal failure.
CONCLUSION: Our clinical report is of significance as it illustrates a possible genotype-phenotype correlation between a specific TSC2 pathogenic variant and a severe renal phenotype. Our case series highlights the importance of establishing genotype-phenotype interactions to provide anticipatory guidance using prognostic data and clinical management.

Keywords: TSC2 ; angiomyolipoma; kidney; pathogenic variant; tuberous sclerosis complex

DOI: https://doi.org/10.1002/mgg3.70205

Front Immunol. 2026 ;17 1700983

TFE3 fusion proteins drive TFE3 rearranged renal cell carcinoma progression via PGC-1α-mediated fatty acid oxidation.

Fan Feng, Yanhao Xu, Zhenggen Deng, Xiang Dong, Guijuan Chen, Wenliang Ma, Dongmei Li, Weidong Gan.

Introduction: TFE3 rearranged renal cell carcinoma (TFE3 rRCC) is a distinct and aggressive subtype of RCC characterized by poor prognosis. While TFE3 fusion proteins are central to its pathogenesis, their specific roles in tumor progression, particularly regarding metabolic regulation, remain incompletely understood. This study investigates whether TFE3 fusion proteins promote TFE3 rRCC progression by regulating fatty acid oxidation (FAO).
Methods: To elucidate the regulatory mechanisms, transcriptome sequencing, Western blotting, real-time quantitative PCR, dual-luciferase reporter assays, Chromatin Immunoprecipitation assays, and Seahorse XF96 analysis were employed to examine how TFE3 fusion proteins regulate the PGC-1α/PPARα/CPT1A axis and its impact on mitochondrial FAO in tumor cells. Additionally, bioinformatics analysis of publicly available TCGA data was conducted to assess the expression of PGC1A and CPT1A in various kidney cancer subtypes and their correlation with patient prognosis.
Results: TFE3 fusion proteins were found to transcriptionally upregulate PGC-1α, thereby increasing the tumor cells dependency on mitochondrial FAO. Mechanistically, PGC-1α co-activated PPARα to promote the expression of CPT1A, a rate-limiting enzyme in FAO. This TFE3/PGC-1α/CPT1A axis enhanced tumor cell proliferation, migration, and invasion. TCGA data analysis revealed that low expression levels of PGC1A and CPT1A in general kidney cancer are associated with poor patient prognosis. Conversely, in our specific TFE3 rRCC cohort, high expression of PGC-1α and CPT1A correlated with poorer survival outcomes, highlighting their clinical significance.
Conclusions: TFE3 fusion proteins enhance FAO and drive TFE3 rRCC progression via the PGC-1α/PPARα/CPT1A axis. Targeting CPT1A could inhibit tumor cell proliferation, suggesting that this pathway may serve as a potential therapeutic target for TFE3 rRCC.

Keywords: PGC1 α; TFE3; cancer progression; fatty acid metabolism; renal cell carcinoma

DOI: https://doi.org/10.3389/fimmu.2026.1700983

Autophagy Rep. 2026 ;5(1): 2624259

TFEB confers resistance against the chemotherapeutic agent CX-5461.

Marjorie Rolland, Benoît Marchand, Laure Bessy, Florence McDuff, Marie-Josée Boucher.

Identifying mechanisms underlying chemoresistance is essential for improving the efficacy of chemotherapeutic drugs. Previously, we showed that cancer cells respond to gemcitabine by activating protective signals dependent on the master regulator of autophagy and lysosomal biogenesis, transcription factor EB (TFEB). However, how gemcitabine triggers these protective responses remains elusive. While gemcitabine primarily aims at disrupting DNA replication, it is also suspected to induce nucleolar stress. In this study, we aimed to examine the effect of gemcitabine on nucleolar stress and investigate whether nucleolar stress inducers could trigger TFEB-dependent protective signals. Besides gemcitabine causing nucleolar stress, the anticancer agent CX-5461, primarily designed to induce nucleolar stress, promoted TFEB nuclear accumulation. Interfering with TFEB improved the sensitivity of cancer cells to both CX-5461 and gemcitabine. Our findings suggest that TFEB provides broad protection against the stress caused by chemotherapeutic drugs, representing a promising target for intercepting chemoresistance and improving the efficacy of anticancer agents.

Keywords: Autophagy; CX-5461; TFEB; chemoresistance; gemcitabine; nucleolar stress

DOI: https://doi.org/10.1080/27694127.2026.2624259

Proc Natl Acad Sci U S A. 2026 Feb 24. 123(8): e2528243123

Reversible acetylation of Hpo regulates the Hippo pathway.

Fengyun Lei, Yan Ding, Yanyun Liu, Hongtan Li, Dafa Zhou, Wenhao Ding, Bin Liu, Xiaohan Sun, Xiaopei Wang, Yunhe Zhao, Qing-Xin Liu, Zizhang Zhou.

The Hippo pathway, which is highly conserved from Drosophila to mammals, plays a crucial role in regulating organ size and tissue homeostasis. Dysregulation of this pathway has been linked to various diseases, including tumors. The pathway controls the subcellular localization of the transcription coactivator Yki through core kinases Hpo and Wts, ultimately influencing the expression of target genes. Extensive studies have shown that most components in this pathway undergo posttranslational modifications, such as phosphorylation and ubiquitination. Nevertheless, the role of acetylation in Hippo signaling is still not fully understood. In this study, we find that Hpo is subject to reversible acetylation by Nej and Hdac3, thereby regulating its stability. Loss of Hdac3 leads to an increase in the expression of Hippo target genes, which is completely rescued by overexpressing Wts, positioning Hdac3 upstream of Wts. Although Hdac3 localizes in both the cell cytoplasm and nucleus, only the cytoplasmic Hdac3 is involved in regulating the Hippo pathway, where it interacts with Hpo to deacetylate and stabilize it. Additionally, knockdown of the acetyltransferase Nej decreases the expression of Hippo target genes, a phenotype that can be reversed by simultaneously silencing Hdac3. Taken together, these findings shed light on the role of reversible acetylation in controlling the Hippo pathway and provide insights into growth regulation and potential therapeutic approaches for related diseases.

Keywords: Hdac3; Hippo pathway; Hpo; Nej; acetylation

DOI: https://doi.org/10.1073/pnas.2528243123