bims-raghud 2024-11-17 papers

Issue of 2024‒11‒17
five papers selected by
Irene Sambri, TIGEM

Expert Opin Ther Targets. 2024 Nov 11. 1-12

ULK1 as a therapeutic target in kidney diseases: Current perspective.

Shruti Shreya, Neha Dagar, Vishwadeep Shelke, Bhupendra Puri, Anil Bhanudas Gaikwad.

INTRODUCTION: Globally, ~850 million people are affected by different kidney diseases. The pathogenesis of kidney diseases is intricate, where autophagy is crucial for maintaining kidney homeostasis. Iteliminates damaged organelles, thus reducing renal lesions and allowing tissue regeneration. Therefore, targeting various autophagy proteins, e.g. Unc-51-like autophagy-activating kinase 1 (ULK1), is emerging as potential therapeutic strategy against kidney disease.AREAS COVERED: This review provides insights into the role of ULK1 as a therapeutic target in kidney diseases. Additionally, we have discussed the recent evidence based on pre-clinical studies for possible novel therapies modulating ULK1-mediated autophagy in kidney diseases.
EXPERT OPINION: ULK1 is one of the critical regulators of autophagy. Moreover, ULK1 works differently for different types of kidney disease. Considering its significant role in kidney disease pathogenesis, it could be a potential target to tackle kidney diseases. However, the dynamic molecular understanding of ULK1 in the context of various kidney diseases is still in its infancy and should be investigated further.

Keywords: Autophagy; ULK1; kidney disease; kidney homeostasis; therapeutic target

DOI: https://doi.org/10.1080/14728222.2024.2421762

Heliyon. 2024 Nov 15. 10(21): e39752

TPC1 regulates melanoma tumourigenesis via mTORC1 and TFEB.

Xuhui Jin, Ali A Hanbashi, Faroq Kamli, Xiaoqi Pan, Colin R Goding, John Parrington.

The major cause of death in cancer patients is a combination of metastatic dissemination combined with therapy resistance. Over recent years, intratumour phenotypic heterogeneity arising from the bi-directional interplay between plastic cancer cells and the microenvironment has been identified as key to disease progression. Most notably metastatic outgrowth and resistance to targeted therapies are frequently associated with activity of mTORC1, a key metabolic hub that promotes protein synthesis and proliferation in the presence of nutrients. Yet while the regulation of mTORC1 by amino acids and glucose availability is well characterized, whether other mechanisms are important in controlling mTORC1 and its downstream signalling is less well understood. Here we show, using the murine B16-F0 melanoma cell line as a model, that mTORC1 activity is decreased following the knockout (KO) of TPC1, a cation channel localised to early and recycling endosomes. Consequently, TPC1 KO melanoma cells exhibit reduced proliferation and invasiveness, as well as increased pigmentation associated with nuclear localisation of the MITF-related transcription factor TFEB. Our results demonstrate that the knockout of TPC1 has induced significant tumour-suppressive effects in melanoma, during which the altered activity of mTORC1 and TFEB play the key roles. The results help us further understand the link between mTORC1 and endolysosomal ion channels, and reveal that TPC1 controls melanoma progression and represents a potential therapeutic target.

Keywords: MITF; Melanoma; TFEB; TPC1; mTORC1

DOI: https://doi.org/10.1016/j.heliyon.2024.e39752

Trends Cell Biol. 2024 Nov 14. pii: S0962-8924(24)00227-7. [Epub ahead of print]

TFEB links the cGAS-STING pathway to lysosome biogenesis.

Yaping Meng, Xinran Li, Haoxing Xu.

The cGAS-STING pathway senses the level of double-stranded (ds)DNA in the cytosol, and is required for innate immunity through its effector, TBK1. A recent study by Lv et al. reports that STING activation also simultaneously promotes lysosomal biogenesis by inducing nuclear translocation of the transcription factors TFEB/TFE3 independent of TBK1.

Keywords: STING; TFEB; cGAS; lysosome

DOI: https://doi.org/10.1016/j.tcb.2024.10.011

Am J Respir Cell Mol Biol. 2024 Nov 08.

Enhanced Gαq Signaling in TSC2-deficient Cells Is Required for Their Neoplastic Behavior.

Aurelie Trefier, Nihad Tousson-Abouelazm, Lama Yamani, Sajida Ibrahim, Kwang-Bo Joung, Adam Pietrobon, Julien Yockell-Lelievre, Terence E Hébert, Reese J Ladak, Tomoko Takano, Mark Nellist, Yoon Namkung, David Chatenet, William L Stanford, Stephane A Laporte, Arnold S Kristof.

Inherited or sporadic loss of the TSC2 gene can lead to pulmonary lymphangioleiomyomatosis (LAM), a rare cystic lung disease caused by protease-secreting interstitial tumor nodules. The nodules arise by metastasis of cells that exhibit features of neural crest and smooth muscle lineage ('LAM cells'). Their aberrant growth is attributed to increased activity of 'mechanistic target of rapamycin complex 1' (mTORC1), an anabolic protein kinase that is normally suppressed by the TSC1-TSC2 protein complex. The mTORC1 inhibitor rapamycin slows the progression of LAM, but fails to eradicate disease, indicating a role for mTORC1-independent mechanisms in LAM pathogenesis. Our previous studies revealed G-protein coupled urotensin-II receptor (UT) signaling as a candidate mechanism, but how it promotes oncogenic signaling in TSC2-deficient cells remained unknown. Using a human pluripotent stem cell-derived in vitro model of LAM, we now show hyperactivation of UT, which was required for their enhanced migration and pro-neoplastic signaling in a rapamycin-insensitive mechanism that required heterotrimeric Gαq/11 (Gαq). Bioluminescence resonance energy transfer assays in HEK 293T cells lacking TSC2 demonstrated selective and enhanced activation of Gαq and its RhoA-associated effectors compared to wild-type control cells. By immunoprecipitation, recombinant UT was physically associated with Gαq and TSC2. The augmented Gαq signaling in TSC2-deleted cells was independent of mTOR activity, and associated with increased endosomal targeting of p63RhoGEF, a known RhoA-activating effector of Gαq. These studies identify potential mTORC1-independent pro-neoplastic mechanisms that can be targeted for prevention or eradication of pulmonary and extrapulmonary LAM tumors.

Keywords: Gαq; Lymphangioleiomyomatosis; Mechanistic target of rapamycin; Tuberous sclerosis complex; Urotensin-II receptor

DOI: https://doi.org/10.1165/rcmb.2024-0111OC

Am J Respir Cell Mol Biol. 2024 Nov 12.

The Bi-Steric Inhibitor RMC-5552 Reduces mTORC1 Signaling and Growth in Lymphangioleiomyomatosis.

Jilly F Evans, Owen A Ledwell, Yan Tang, Ryan Rue, Alexander R Mukhitov, Rémi Diesler, Susan M Lin, Swaroop V Kanth, Maria C Basil, Edward Cantu, Elizabeth P Henske, Vera P Krymskaya.

Mutations in the Tuberous Sclerosis Complex (TSC) genes result in the hyperactivation of the mechanistic/mammalian target of rapamycin 1 (mTORC1) growth pathway in mesenchymal pulmonary cells. Rapamycin (SirolimusTM), a naturally occurring macrolide, is the only therapeutic approved for women with lymphangioleiomyomatosis (LAM), a progressive, destructive lung disease caused by TSC gene mutations and mTORC1 hyperactivation. However, on cessation of the drug, lung function decline continues. We demonstrated here that pulmonary LAM cancer stem-like cells (SLS) most highly expressed the eukaryotic translation initiation factor 4E (eIF4E)-dependent translation initiation genes. We also showed that the eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) gene has the lowest expression in these cells, indicating that the 4E-BP1/eIF4E ratio in LAM SLS cells favors unrestrained eIF4E oncogenic mRNA translation. The bi-steric mTORC1-selective compound RMC-5552 prevented growth of LAM-associated fibroblasts (LAFs) and phosphorylation of proteins in the ribosomal protein S6K1/ribosomal protein S6 (S6K1/S6) and 4E-BP1/eIF4E translation mTORC1-driven pathways, whereas rapamycin only blocked the S6K/S6 axis. Rapamycin inhibition of LAF growth was rapidly reversed, but RMC-5552 inhibition was more durable. RMC-5552, through its potential to eradicate LAM cancer SLS cells, may have therapeutic benefit in LAM and other diseases with mTORC1 hyperactivity.

Keywords: RMC-5552 bi-steric inhibitor; TSC2; lymphangioleiomyomatosis; mTORC1; rapamycin

DOI: https://doi.org/10.1165/rcmb.2024-0242OC