bims-raghud 2025-01-12 papers

bims-raghud

Biomed News

on RagGTPases in human diseases

Issue of 2025–01–12
nine papers selected by
Irene Sambri, TIGEM

Serinc2 antagonizes pressure overload-induced cardiac hypertrophy via regulating the amino acid/mTORC1 signaling pathway.
Deciphering the Power of Resveratrol in Mitophagy: From Molecular Mechanisms to Therapeutic Applications.
Restoring Autophagy by Exercise Ameliorates Insulin Resistance Partly via Calcineurin-Driven TFEB Nuclear Translocation.
Ubiquitination of TFEB increased intestinal permeability to aggravate metabolic dysfunction-associated steatohepatitis.
Two FAM134B isoforms differentially regulate ER dynamics during myogenesis.
Wnt Signaling Pathway in Tumor Biology.
Amino acids and KLHL22 do not activate mTORC1 via DEPDC5 degradation.
Non-cell-autonomous regulation of mTORC2 by Hedgehog signaling maintains lipid homeostasis.
Functional specialization of MITF, TFEB and TFE3 drives radically distinct adaptive gene expression programs in melanoma.

Biochim Biophys Acta Mol Basis Dis. 2025 Jan 03. pii: S0925-4439(24)00644-6. [Epub ahead of print]1871(3): 167650

Serinc2 antagonizes pressure overload-induced cardiac hypertrophy via regulating the amino acid/mTORC1 signaling pathway.

Shuai Mao, Manqi Yang, Huimin Liu, Shun Wang, Man Liu, Shan Hu, Beilei Liu, Hao Ju, Zheyu Liu, Min Huang, Shuijing He, Mian Cheng, Gang Wu.

   BACKGROUND: Cardiac hypertrophy is characterized by the upregulation of fetal genes, increased protein synthesis, and enlargement of cardiac myocytes. The mechanistic target of rapamycin complex 1 (mTORC1), which responds to fluctuations in cellular nutrient and energy levels, plays a pivotal role in regulating protein synthesis and cellular growth. While attempts to inhibit mTORC1 activity, such as through the application of rapamycin and its analogs, have demonstrated limited efficacy, further investigation is warranted.
METHODS AND RESULTS: Here, we show that Serinc2 expression is downregulated in the transverse aortic constriction (TAC)-induced hypertrophic myocardium. Both in vivo and in vitro, the reduction of Serinc2 expression results in pathological hypertrophic growth, whereas Serinc2 overexpression exhibits a protective effect. RNA sequencing analysis following Serinc2 knockdown reveals a transcriptomic shift toward a pro-hypertrophic profile and suggests a significant interplay between Serinc2, amino acid, mTOR, and the lysosome, a hub for mTOR activation. Moreover, we show that Serinc2 localizes to lysosomes and hinders mTORC1 recruitment to the lysosomal membrane in response to amino acid stimulation, playing a critical role in regulating amino acid signaling pathway involved in the activation of p70S6K, S6, and 4EBP1 in Hela cells. And its deficiency exacerbates mTORC1 activity and mTORC1-dependent subsequent protein synthesis, which can be abrogated by rapamycin. In line with our in vitro findings, Serinc2 knockout mice subjected to TAC surgery exhibit elevated phosphorylation of p70S6K and 4EBP1, while inhibition of mTORC1 signaling through amino acid deprivation prevents this activation and impedes the progression to pathological cardiac remodeling.
CONCLUSIONS: We have illustrated that Serinc2 localizes to the lysosomal membrane and modulates amino acid /mTORC1 signaling in cardiomyocytes. Serinc2 therefore presents a potential therapeutic target for mitigating excessive protein synthesis and improving heart failure under hemodynamic stress.

Keywords:  Amino acid; Cardiac hypertrophy; Lysosome; SERINC2; mTORC1

DOI:  https://doi.org/10.1016/j.bbadis.2024.167650
Phytother Res. 2025 Jan 04.

Deciphering the Power of Resveratrol in Mitophagy: From Molecular Mechanisms to Therapeutic Applications.

Hongmei Liu, Yixuan Song, Huan Wang, Ying Zhou, Min Xu, Jiaxun Xian.

  Resveratrol (RES), a natural polyphenolic compound, has garnered significant attention for its therapeutic potential in various pathological conditions. This review explores how RES modulates mitophagy-the selective autophagic degradation of mitochondria essential for maintaining cellular homeostasis. RES promotes the initiation and execution of mitophagy by enhancing PINK1/Parkin-mediated mitochondrial clearance, reducing reactive oxygen species production, and mitigating apoptosis, thereby preserving mitochondrial integrity. Additionally, RES regulates mitophagy through the activation of key molecular targets such as AMP-activated protein kinase (AMPK), the mechanistic target of rapamycin (mTOR), deacetylases (SIRT1 and SIRT3), and mitochondrial quality control (MQC) pathways, demonstrating substantial therapeutic effects in multiple disease models. We provide a detailed account of the biosynthetic pathways, pharmacokinetics, and metabolic characteristics of RES, focusing on its role in mitophagy modulation and implications for medical applications. Potential adverse effects associated with its clinical use are also discussed. Despite its promising therapeutic properties, the clinical application of RES is limited by issues of bioavailability and pharmacokinetic profiles. Future research should concentrate on enhancing RES bioavailability and developing derivatives that precisely modulate mitophagy, thereby unlocking new avenues for disease therapy.

Keywords:  AMPK; PINK1/Parkin; SIRT1; disease intervention; mitophagy; resveratrol

DOI:  https://doi.org/10.1002/ptr.8433
Clin Exp Pharmacol Physiol. 2025 Mar;52(3): e70010

Restoring Autophagy by Exercise Ameliorates Insulin Resistance Partly via Calcineurin-Driven TFEB Nuclear Translocation.

Ping Wang, Jiaxin Li, Chun Guang Li, Xian Zhou, Xiaolong Chen, Minghua Zhu, Hongjiang Wang.

  Exercise activates autophagy and lysosome system in skeletal muscle, which are known to play an important role in metabolic adaptation. However, the mechanism of exercise-activated autophagy and lysosome system in obese insulin resistance remains covert. In this study, we investigated the role of exercise-induced activation of autophagy and lysosome system in improving glucose metabolism of skeletal muscle. Male C57BL/6 mice were randomly divided into five groups: the chow diet (CD) group, the high-fat diet (HFD) group, the high-fat diet plus exercise (HFD-E) group and the HFD-E treated with calcineurin inhibitor FK506 (HFD-E-F) or saline (HFD-E-S) groups. The mice in exercise groups (HFD-E, HFD-E-F and HFD-E-S) were subjected to aerobic treadmill exercise (speed at 12 m/min for 1 h per session, 0° slope, 5 days per week for 12 weeks). Mice of HFD-E-F group were intraperitoneally administered FK506 (1 mg/kg), once each day for 2 weeks before the end of exercise. Expressions pTFEB, T-TFEB and autophagy-lysosome markers, including Beclin1, LC3, ULK1, SQSTM1, LAMP1, CTSD and CTSL proteins in gastrocnemius muscle were analysed. We demonstrated that HFD induced insulin resistance and decreased autophagy-lysosomal proteins and the exercise significantly increased transcription factor EB (TFEB) translocation from the cytoplasm to the nucleus, restored the impaired autophagy-lysosomal-related protein expressions, and improved glucose metabolism. The increase in TFEB nuclear translocation was partly blocked by the calcineurin inhibitor FK506. Our results suggest that exercise promotes autophagy and lysosome restoration by regulating calcineurin-mediated TFEB nuclear translocation, ultimately alleviating HFD-induced insulin resistance in mice skeletal muscle.

Keywords:  TFEB; autophagy and lysosome dysfunction; exercise; insulin resistance

DOI:  https://doi.org/10.1111/1440-1681.70010
Hepatology. 2025 Jan 10.

Ubiquitination of TFEB increased intestinal permeability to aggravate metabolic dysfunction-associated steatohepatitis.

Donghai Liu, Lang Chen, Zai Wang, Zecheng Li, Lihong Liu, Liang Peng.

BACKGROUND AND AIMS: Increased intestinal permeability exacerbates the development of metabolic dysfunction associated steatohepatitis (MASH), but the underlying mechanisms remain unclear. Autophagy is important for maintaining normal intestinal permeability. Here, we investigated the impact of intestinal transcription factor EB (TFEB), a key regulator of autophagy, in intestinal permeability and MASH progression.
METHODS: TFEB expression was analyzed in the proximal colon of 45 individuals with metabolic dysfunction associated steatotic liver disease and 23 healthy controls. We utilized immunoprecipitation-mass spectrometry toidentify TFEB-interacting proteins. Intestine-specific Tfeb knockout mice were generated by mating Tfebfl/fl mice with Villin-Cre mice. The mice were fed a high-fat, high-sucrose diet, and assessments were performed to evaluate intestinal permeability and MASH progression.
RESULTS: Intestinal TFEB levels were reduced in MASH patients and negatively correlated with intestinal permeability and hepatic toxicity. Intestine-specific TFEB deficiency increased intestinal permeability and worsened MASH severity, whereas moderate TFEB overexpression conferred protective effects. Mechanistically, the E3 ligase TRIP12 promotes the ubiquitination and degradation of nuclear TFEB, thereby inhibiting autophagic flux to aggravate intestinal barrier impairment and subsequently promote MASH progression. Importantly, a peptide PT1 designed to block the TRIP12-TFEB interaction reduced MASH progression.
CONCLUSIONS: The ubiquitination of TFEB plays a pivotal role in increasing intestinal permeability and promoting the progression of MASH by inhibiting autophagy. Intestinal TFEB may represent a novel therapeutic target for the treatment of MASH.

DOI: https://doi.org/10.1097/HEP.0000000000001214
EMBO J. 2025 Jan 06.

Two FAM134B isoforms differentially regulate ER dynamics during myogenesis.

Viviana Buonomo, Kateryna Lohachova, Alessio Reggio, Sara Cano-Franco, Michele Cillo, Lucia Santorelli, Rossella Venditti, Elena Polishchuk, Ivana Peluso, Lorene Brunello, Carmine Cirillo, Sara Petrosino, Malan Silva, Rossella De Cegli, Sabrina Di Bartolomeo, Cesare Gargioli, Paolo Swuec, Mirko Cortese, Alexandra Stolz, Ramachandra M Bhaskara, Paolo Grumati.

  Endoplasmic reticulum (ER) plasticity and ER-phagy are intertwined processes essential for maintaining ER dynamics. We investigated the interplay between two isoforms of the ER-phagy receptor FAM134B in regulating ER remodeling in differentiating myoblasts. During myogenesis, the canonical FAM134B1 is degraded, while its isoform FAM134B2 is transcriptionally upregulated. The switch, favoring FAM134B2, is an important regulator of ER morphology during myogenesis. FAM134B2 partial reticulon homology domain, with its rigid conformational characteristics, enables efficient ER reshaping. FAM134B2 action increases in the active phase of differentiation leading to ER restructuring via ER-phagy, which then reverts to physiological levels when myotubes are mature and the ER is reorganized. Knocking out both FAM134B isoforms in myotubes results in an aberrant proteome landscape and the formation of dilated ER structures, both of which are rescued by FAM134B2 re-expression. Our results underscore how the fine-tuning of FAM134B isoforms and ER-phagy orchestrate the ER dynamics during myogenesis providing insights into the molecular mechanisms governing ER homeostasis in muscle cells.

Keywords:  Autophagy; Endoplasmic Reticulum; FAM134B; Myogenesis; Reticulophagy

DOI:  https://doi.org/10.1038/s44318-024-00356-2
Genes (Basel). 2024 Dec 13. pii: 1597. [Epub ahead of print]15(12):

Wnt Signaling Pathway in Tumor Biology.

Sabina Iluta, Madalina Nistor, Sanda Buruiana, Delia Dima.

  Relapse and metastasis are the major challenges that stand in the way of cancer healing and survival, mainly attributed to cancer stem cells (CSCs). Their capabilities of self-renewal and tumorigenic potential leads to treatment resistance development. CSCs function through signaling pathways such as the Wnt/β-catenin cascade. While commonly involved in embryogenesis and adult tissues homeostasis, the dysregulation of the Wnt pathway has direct correlations with tumorigenesis, metastasis, and drug resistance. The development of therapies that target CSCs and bulk tumors is both crucial and urgent. However, the extensive crosstalk present between Wnt and other signaling networks (Hedgehog and Notch) complicates the development of efficient long-term therapies with minimal side-effects on normal tissues. Despite the obstacles, the emergence of Wnt inhibitors and subsequent modulation of the signaling pathways would provide dynamic therapeutic approaches to impairing CSCs and reversing resistance mechanisms.

Keywords:  Wnt pathway; cancer stem cells; tumor biology

DOI:  https://doi.org/10.3390/genes15121597
Nature. 2025 Jan;637(8045): E11-E14

Amino acids and KLHL22 do not activate mTORC1 via DEPDC5 degradation.

Max L Valenstein, Pranav V Lalgudi, Jibril F Kedir, Kendall J Condon, Anna Platzek, Daniel G Freund, Martin S Taylor, Yunhan Xu, Raghu R Chivukula, David M Sabatini.

DOI: https://doi.org/10.1038/s41586-024-07974-0
Cell Rep. 2025 Jan 07. pii: S2211-1247(24)01542-0. [Epub ahead of print]44(1): 115191

Non-cell-autonomous regulation of mTORC2 by Hedgehog signaling maintains lipid homeostasis.

Kylie R VanDerMolen, Martin A Newman, Peter C Breen, Yunjing Gao, Laura A Huff, Robert H Dowen.

  Organisms allocate energetic resources between essential cellular processes to maintain homeostasis and, in turn, maximize fitness. The nutritional regulators of energy homeostasis have been studied in detail; however, how developmental signals might impinge on these pathways to govern metabolism is poorly understood. Here, we identify a non-canonical role for Hedgehog (Hh), a classic regulator of development, in maintaining intestinal lipid homeostasis in Caenorhabditis elegans. We demonstrate, using C. elegans and mouse hepatocytes, that Hh metabolic regulation does not occur through the canonical Hh transcription factor TRA-1/GLI, but rather via non-canonical signaling that engages mammalian target of rapamycin complex 2 (mTORC2). Hh mutants display impaired lipid homeostasis, decreased growth, and upregulation of autophagy factors, mimicking loss of mTORC2. Additionally, we find that Hh inhibits p38 MAPK signaling in parallel to mTORC2 activation to modulate lipid homeostasis. Our findings reveal a non-canonical role for Hh signaling in lipid metabolism via regulation of core homeostatic pathways.

Keywords:  C. elegans; CP: Metabolism; Hedgehog; LIN-29; autophagy; growth; hepatocytes; lipid metabolism; mTORC2; p38; vitellogenesis

DOI:  https://doi.org/10.1016/j.celrep.2024.115191
bioRxiv. 2024 Dec 23. pii: 2024.12.23.629393. [Epub ahead of print]

Functional specialization of MITF, TFEB and TFE3 drives radically distinct adaptive gene expression programs in melanoma.

Diogo Dias, Erica Oliveira, Román Martí-Díaz, Sarah Andrews, Ana Chocarro-Calvo, Alice Bellini, Laura Mosteo, Yurena Vivas García, Jagat Chauhan, Linxin Li, José Manuel García-Martinez, José Neptuno Rodriguez-López, Silvya Stuchi Maria-Engler, Custodia García-Jiménez, Luis Sanchez-Del-Campo, Pakavarin Louphrasitthiphol, Colin R Goding.

Within cells multiple related transcription factors targeting the same sequences may co-exist, leading to potential regulatory cooperativity, redundancy or competition. Yet the differential roles and biological functions of co-targeting transcription factors is poorly understood. In melanoma, three highly-related transcription factors are co-expressed: The mTORC1-regulated TFEB and TFE3, that are key effectors of a wide range of metabolic and microenvironmental cues; and MITF, that controls melanoma phenotypic identity. Here we reveal the functional specialization of MITF, TFE3 and TFEB and their impact on cancer progression. Notably, although all bind the same sequences, each regulates radically different and frequently opposing gene expression programs to coordinate differentiation, metabolic reprogramming, protein synthesis, and expression of immune modulators. The results uncover a hierarchical cascade in which microenvironmental stresses, including glucose limitation, lead MITF, TFEB and TFE3 to drive distinct biologically important transcription programs that underpin phenotypic transitions in cancer.

DOI: https://doi.org/10.1101/2024.12.23.629393