bims-raghud Biomed News
on RagGTPases in human diseases
Issue of 2025–09–21
six papers selected by
Irene Sambri, TIGEM
  1. Structural basis for mTORC1 activation on the lysosomal membrane.
  2. mTOR inhibition reprograms cellular lipid homeostasis by inducing alternative lipid uptake and promoting cholesterol transport.
  3. Multifaceted role of AMPK in autophagy: more than a simple trigger?
  4. TOR signaling on membranes.
  5. SGLT2 Inhibitors as a Therapeutic Option for Both Acute and Chronic Refractory Hypomagnesemia in Diabetic and Nondiabetic Patients: A Multicenter Case Series.
  6. Inhibition of Tumor Lipogenesis and Growth by Peptide-Based Targeting of SREBP Activation.
  1. Nature. 2025 Sep 17.
    Structural basis for mTORC1 activation on the lysosomal membrane.
    Zhicheng Cui, Alessandra Esposito, Gennaro Napolitano, Andrea Ballabio, James H Hurley.
      The mechanistic target of rapamycin complex 1 (mTORC1) integrates growth factor (GF) and nutrient signals to stimulate anabolic processes connected to cell growth and inhibit catabolic processes such as autophagy1,2. GF signalling through the tuberous sclerosis complex regulates the lysosomally localized small GTPase RAS homologue enriched in brain (RHEB)3. Direct binding of RHEB-GTP to the mTOR kinase subunit of mTORC1 allosterically activates the kinase by inducing a large-scale conformational change4. Here we reconstituted mTORC1 activation on membranes by RHEB, RAGs and Ragulator. Cryo-electron microscopy showed that RAPTOR and mTOR interact directly with the membrane. Full engagement of the membrane anchors is required for optimal alignment of the catalytic residues in the mTOR kinase active site. Converging signals from GFs and nutrients drive mTORC1 recruitment to and activation on lysosomal membrane in a four-step process, consisting of (1) RAG-Ragulator-driven recruitment to within ~100 Å of the lysosomal membrane; (2) RHEB-driven recruitment to within ~40 Å; (3) RAPTOR-membrane engagement and intermediate enzyme activation; and (4) mTOR-membrane engagement and full enzyme activation. RHEB and membrane engagement combined leads to full catalytic activation and structurally explains GF and nutrient signal integration at the lysosome.
    DOI:  https://doi.org/10.1038/s41586-025-09545-3
  2. Mol Cell. 2025 Sep 18. pii: S1097-2765(25)00706-3. [Epub ahead of print]85(18): 3486-3504.e7
    mTOR inhibition reprograms cellular lipid homeostasis by inducing alternative lipid uptake and promoting cholesterol transport.
    Sejeong Shin, Min-Joon Han, Ishika Patel, Alia M Welsh, Maria Sverdlov, Wonhwa Cho, Stephanie M Cologna, Philippe P Roux, Sang-Oh Yoon.
      The mechanistic target of rapamycin (mTOR) is a key regulator of lipid homeostasis by controlling processes including lipid uptake and biosynthesis. mTOR dysregulation and consequent altered lipid metabolism are common in various diseases, including cancers, making mTOR a promising therapeutic target. Therefore, it is crucial to understand how mTOR activation and inhibition reprogram lipid homeostasis. In human cancer cell lines, mTOR inhibition induces alternative lipid uptake through translation eukaryotic initiation factor 3D (eIF3D)-mediated low-density lipoprotein receptor (LDLR)-related protein 6 (LRP6) increase and activates liver X receptor β (LXRβ), promoting cholesterol release from lysosomes and its transport to the plasma membrane via Niemann-Pick disease type C (NPC) intracellular cholesterol transporter 1 (NPC1). This signaling supports tumor cell survival and stress resistance. In mouse xenograft models, combining mTOR inhibition with LRP6 knockdown or NPC1 targeting significantly suppresses tumor growth. Our findings highlight mTOR feedback signaling in reprogramming lipid homeostasis and its therapeutic potential to treat diseases characterized by dysregulated mTOR.
    Keywords:  AKT; IGF1R; LRP6; NPC1; cholesterol; mTOR
    DOI:  https://doi.org/10.1016/j.molcel.2025.08.021
  3. Am J Physiol Cell Physiol. 2025 Sep 15.
    Multifaceted role of AMPK in autophagy: more than a simple trigger?
    Milos Mandic, Maja Misirkic Marjanovic, Kristina Janjetovic, Mihajlo Bosnjak, Ljubica Harhaji-Trajkovic, Vladimir Trajkovic, Ljubica Vucicevic.
      AMP-activated protein kinase (AMPK) is a key sensor and regulator of intracellular energy balance. During energy stress, AMPK helps restore cellular ATP levels by preventing anabolic and promoting catabolic processes, such as autophagy. AMPK activates autophagy both post-translationally and transcriptionally, by suppressing the mechanistic target of rapamycin complex 1 activity and stimulating the activation of unc-51 like autophagy activating kinase (ULK), autophagosome-lysosome fusion, and expression of autophagy-related genes. Recent research, however, suggests an unexpected role of AMPK in energy stress, where AMPK inhibits ULK and suppresses ATP-consuming autophagic response, possibly to save energy and maintain the autophagic machinery for subsequent activation once the stress subsides. The present review elucidates this dual nature of AMPK in autophagy regulation while highlighting its molecular mechanisms and importance for therapeutic approaches involving AMPK modulation.
    Keywords:  AMPK; ULK1/2; autophagy; energy metabolism; energy stress
    DOI:  https://doi.org/10.1152/ajpcell.01058.2024
  4. FEBS Lett. 2025 Sep 19.
    TOR signaling on membranes.
    Robbie Loewith, Lucas Tafur.
      The Target of Rapamycin (TOR) is a highly conserved protein kinase that regulates cell growth and metabolism through two distinct complexes, TORC1 and TORC2. Each complex regulates different downstream targets; however, both are activated and regulated on lipid membranes. In this Perspective, we will revise the structural biology of TOR complexes and the molecular mechanisms governing their regulation, highlighting the importance of lipid membranes for their function.
    Keywords:  (m)TORC1; (m)TORC2; cryoEM; lipid membrane; peripheral membrane protein complexes
    DOI:  https://doi.org/10.1002/1873-3468.70171
  5. Case Rep Nephrol. 2025 ;2025 5615339
    SGLT2 Inhibitors as a Therapeutic Option for Both Acute and Chronic Refractory Hypomagnesemia in Diabetic and Nondiabetic Patients: A Multicenter Case Series.
    Fatima Ayub, Praveen Errabelli, Abedalrahman Almashayekh, Ahmed Abdallah, Md Rajibul Hasan, Manisha Singh, Nithin Karakala, Joseph Hunter Holthoff.
      Sodium-glucose cotransporter 2 (SGLT2) inhibitors are widely used in patients with kidney disease and have been shown to increase serum magnesium levels. Case reports have described their role in correcting hypomagnesemia; however, there is limited evidence regarding their efficacy in patients with renal magnesium wasting. Furthermore, data regarding their role in acute treatment and sustained efficacy to treat hypomagnesemia are lacking. We present a multicenter retrospective, observational case series from two U.S. medical centers describing five patients with refractory hypomagnesemia who experienced significant improvement following initiation of SGLT2 inhibitors. Patients 1-4 showed marked renal magnesium wasting with severe symptomatic hypomagnesemia which responded robustly to SGLT2 inhibitor therapy. Even though Patient 5 did not have renal magnesium wasting, hypomagnesemia still improved with the addition of an SGLT2 inhibitor. Furthermore, the addition of an SGLT2 inhibitor acutely improved the hypomagnesemia of Patients 1 and 2 in an inpatient setting, and Patients 3-5 demonstrated sustained improvement of hypomagnesemia across extended outpatient follow-up. The improvement of hypomagnesemia was irrespective of the diabetic status of the patient. All cases resulted in substantial reduction or cessation of magnesium (Mg) supplementation. These findings suggest a novel therapeutic application of SGLT2 inhibitors for managing intractable hypomagnesemia, both acutely and chronically, regardless of the diabetes being the primary culprit.
    DOI:  https://doi.org/10.1155/crin/5615339
  6. Adv Sci (Weinh). 2025 Sep 17. e08111
    Inhibition of Tumor Lipogenesis and Growth by Peptide-Based Targeting of SREBP Activation.
    Shudi Luo, Huang Yang, Xiaoming Jiang, Zheng Wang, Xuxiao He, Ying Meng, Shan Li, Min Li, Daqian Xu, Zhengwei Mao, Zhimin Lu.
      Tumor cells have substantially increased lipid biogenesis, which is primarily regulated by the activation of sterol regulatory element-binding protein (SREBP). However, whether SREBP regulation can be targeted for cancer treatment remains unclear. Here, it is demonstrated that treating tumor cells with a peptide that replicates the amino acid sequence in Insig1/2 loop 1, which is the region where Insig1/2 interacts with AKT-phosphorylated phosphoenolpyruvate carboxykinase 1 (PCK1), inhibits the IGF1-induced interaction between PCK1 and Insig1/2. Consequently, this treatment abrogates PCK1-mediated phosphorylation of Insig1 at S207 and Insig2 at S151, reduces the nuclear accumulation of SREBP1, and decreases SREBP1 activity-dependent expression of lipid synthesis genes, lipid accumulation, and tumor cell proliferation. Intravenous administration of engineered liposomal nanoparticles (LNP)-encapsulated Insig1/2 loop 1 peptide effectively suppresses tumor growth and extends mouse survival without apparent adverse effects. The peptide treatment, when combined with the receptor tyrosine kinase inhibitor lenvatinib or the anti-obesity medication semaglutide, results in additive tumor inhibition. These findings highlight the potential of LNP-Insig1/2 loop 1 peptide administration to inhibit SREBP activity-traditionally regarded as untargetable-for the treatment of human cancer.
    Keywords:  Insig1/2; LNP; PCK1; SREBP1; fatty acid synthesis; peptide; tumorigenesis
    DOI:  https://doi.org/10.1002/advs.202508111
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