bims-raghud 2024-12-29 papers

Issue of 2024–12–29
four papers selected by
Irene Sambri, TIGEM

J Biol Chem. 2024 Dec 21. pii: S0021-9258(24)02624-3. [Epub ahead of print] 108122

Calmodulin enhances mTORC1 signaling by preventing TSC2-Rheb binding.

Yuna Amemiya, Yuichiro Ioi, Makoto Araki, Kenji Kontani, Masatoshi Maki, Hideki Shibata, Terunao Takahara.

The mechanistic target of rapamycin complex 1 (mTORC1) functions as a master regulator of cell growth and proliferation. We previously demonstrated that intracellular calcium ion (Ca2+) concentration modulates the mTORC1 pathway via binding of the Ca2+ sensor protein calmodulin (CaM) to tuberous sclerosis complex 2 (TSC2), a critical negative regulator of mTORC1. However, the precise molecular mechanism by which Ca2+/CaM modulates mTORC1 activity remains unclear. Here, we performed a binding assay based on nano-luciferase reconstitution, a method for detecting weak interactions between TSC2 and its target, Ras homolog enriched in brain (Rheb), an activator of mTORC1. CaM inhibited the binding of TSC2 to Rheb in a Ca2+-dependent manner. Live-cell imaging analysis indicated increased interaction between the CaM-binding region of TSC2 and CaM in response to elevated intracellular Ca2+ levels. Furthermore, treatment with carbachol, an acetylcholine analog, elevated intracellular Ca2+ levels, and activated mTORC1. Notably, carbachol-induced activation of mTORC1 was inhibited by CaM inhibitors, corroborating the role of Ca2+/CaM in promoting the mTORC1 pathway. Consistent with the effect of Ca2+/CaM on the TSC2-Rheb interaction, increased intracellular Ca2+ concentration promoted the dissociation of TSC2 from lysosomes without affecting Akt-dependent phosphorylation of TSC2, suggesting that the regulatory mechanism of TSC2 by Ca2+/CaM is distinct from the previously established action mechanism of TSC2. Collectively, our findings offer mechanistic insights into TSC2-Rheb regulation mediated by Ca2+/CaM, which links Ca2+ signaling to mTORC1 activation.

Keywords: Rheb; calcium; calmodulin; mechanistic target of rapamycin complex 1; tuberous sclerosis complex

DOI: https://doi.org/10.1016/j.jbc.2024.108122

Front Cell Dev Biol. 2024 ;12 1499457

The pro-fibrotic role of autophagy in renal intrinsic cells: mechanisms and therapeutic potential in chronic kidney disease.

Ying-Ying Zhang, Xiao-Tao Zhou, Geng-Zhen Huang, Wen-Jun Liao, Xian Chen, Yue-Rong Ma.

Chronic kidney disease (CKD) represents a significant global public health burden, affecting over 10% of the world's population. Its high morbidity, multifactorial complications, and substantial mortality impose significant burdens on healthcare systems and patients, necessitating considerable investment in healthcare resources. Renal fibrosis (RF) is a key pathological feature and driver of CKD progression. Extensive research indicates that autophagy participates in the complete pathogenesis of RF. Under physiological conditions, autophagy is essential for maintaining renal cellular homeostasis. However, under pathological conditions, perhaps aberrant and sustained activation of autophagy contributes to oxidative stress, apoptosis, inflammation, etc. Ultimately, they accelerate the development of RF. The role of autophagy in RF is currently controversial. This review investigates the molecular mechanisms by which intrinsic renal cell autophagy contributes to RF across diverse disease models, suggesting that autophagy and its associated regulatory pathways represent potential diagnostic and therapeutic targets for CKD.

Keywords: autophagy; chronic kidney disease; mechanism; renal fibrosis; therapeutic targets

DOI: https://doi.org/10.3389/fcell.2024.1499457

Dev Cell. 2024 Dec 21. pii: S1534-5807(24)00727-5. [Epub ahead of print]

TFEB triggers a matrix degradation and invasion program in triple-negative breast cancer cells upon mTORC1 repression.

David Remy, Sandra Antoine-Bally, Sophie de Toqueville, Célia Jolly, Anne-Sophie Macé, Gabriel Champenois, Fariba Nemati, Isabel Brito, Virginie Raynal, Amulya Priya, Adèle Berlioz, Ahmed Dahmani, André Nicolas, Didier Meseure, Elisabetta Marangoni, Philippe Chavrier.

The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is frequently hyperactivated in triple-negative breast cancers (TNBCs) associated with poor prognosis and is a therapeutic target in breast cancer management. Here, we describe the effects of repression of mTOR-containing complex 1 (mTORC1) through knockdown of several key mTORC1 components or with mTOR inhibitors used in cancer therapy. mTORC1 repression results in an ∼10-fold increase in extracellular matrix proteolytic degradation. Repression in several TNBC models, including in patient-derived xenografts (PDXs), induces nuclear translocation of transcription factor EB (TFEB), which drives a transcriptional program that controls endolysosome function and exocytosis. This response triggers a surge in endolysosomal recycling and the surface exposure of membrane type 1 matrix metalloproteinase (MT1-MMP) associated with invadopodia hyperfunctionality. Furthermore, repression of mTORC1 results in a basal-like breast cancer cell phenotype and disruption of ductal carcinoma in situ (DCIS)-like organization in a tumor xenograft model. Altogether, our data call for revaluation of mTOR inhibitors in breast cancer therapy.

Keywords: MT1-MMP; TFEB; extracellular matrix; invadopodia; mTOR inhibitors; mTORC1; patient-derived xenograft; triple-negative breast cancer; tumor invasion

DOI: https://doi.org/10.1016/j.devcel.2024.12.005

Genes Dis. 2025 Mar;12(2): 101260

mTOR pathway: A key player in diabetic nephropathy progression and therapeutic targets.

Jingxuan Shi, Xinze Liu, Yuanyuan Jiao, Jingwei Tian, Jiaqi An, Guming Zou, Li Zhuo.

Diabetic nephropathy is a prevalent complication of diabetes and stands as the primary contributor to end-stage renal disease. The global prevalence of diabetic nephropathy is on the rise, however, due to its intricate pathogenesis, there is currently an absence of efficacious treatments to enhance renal prognosis in affected patients. The mammalian target of rapamycin (mTOR), a serine/threonine protease, assumes a pivotal role in cellular division, survival, apoptosis delay, and angiogenesis. It is implicated in diverse signaling pathways and has been observed to partake in the progression of diabetic nephropathy by inhibiting autophagy, promoting inflammation, and increasing oxidative stress. In this academic review, we have consolidated the understanding of the pathological mechanisms associated with four distinct resident renal cell types (podocytes, glomerular mesangial cells, renal tubular epithelial cells, and glomerular endothelial cells), as well as macrophages and T lymphocytes, within a diabetic environment. Additionally, we highlight the research progress in the treatment of diabetic nephropathy with drugs and various molecules interfering with the mTOR signaling pathway, providing a theoretical reference for the treatment and prevention of diabetic nephropathy.

Keywords: Bibliometrics; Diabetic nephropathy; Glomerular endothelial cell; Immune cell; Mesangial cell; Podocyte; Renal tubular epithelial cell; mTOR

DOI: https://doi.org/10.1016/j.gendis.2024.101260