bims-lycede 2026-01-25 papers

Cell Commun Signal. 2026 Jan 20.

Peripheral lysosome levels dictate mTORC1 inactivation even when catabolically impaired.

Huy Quang Dang, Therése Forssén, Spyridon Pantelios, Aisegkioul Nteli Chatzioglou, Ewa Kurzejamska, C Theresa Vincent, Yasir Ibrahim, Anders P Mutvei.

The mechanistic target of rapamycin complex 1 (mTORC1) is a central driver of cell growth that is frequently hyperactivated in cancer. While mTORC1 is activated at the lysosomal surface in response to growth factors and amino acids, the processes governing its inactivation are not fully understood. Here, we report that sustained mTORC1 suppression during leucine or arginine starvation requires the translocation of peripheral lysosomes to the perinuclear region. Our data suggest that a pool of mTOR remains active at peripheral lysosomes during starvation, and that increased spatial separation between lysosomes and the plasma membrane attenuates PI3K/Akt signaling-thereby reducing inputs that otherwise maintain mTORC1 activity. Consequently, preventing lysosome translocation and increasing peripheral lysosome levels sustains mTORC1 signaling during prolonged starvation in a PI3K/Akt-dependent manner independently of autophagy. Under these conditions, mTORC1 signaling persists even when lysosomal catabolism is perturbed by chloroquine or concanamycin A. Collectively, these data indicate that the peripheral lysosome pool, even when catabolically impaired, can sustain mTORC1 signaling under nutrient scarcity, by modulating PI3K/Akt signaling input to the pathway. These observations identify peripheral lysosome levels as a critical determinant of mTORC1 inactivation during nutrient stress and may have implications for diseases with aberrant mTORC1 signaling, including cancer.

Keywords: Amino acid deprivation; Catabolically impaired lysosomes; Lysosome positioning; MTORC1; PI3K-Akt signaling; Rab7; Rap1

DOI: https://doi.org/10.1186/s12964-026-02659-9

Chem Biol Interact. 2026 Jan 20. pii: S0009-2797(26)00040-2. [Epub ahead of print] 111932

Thalidezine triggers Cathepsin B-mediated cell death in T-cell lymphoma by disrupting lysosomal function.

Yingjie Qing, Su Xu, Dawei Yang, Jie Liu, Hui Cao.

T-cell lymphoma (TCL) is an aggressive malignancy defined by poor prognosis and therapeutic resistance, demanding innovative strategies. Targeting the lysosome to induce cell death has emerged as a powerful anti-cancer strategy, however its potential as a therapeutic target in TCL is yet to be fully developed. Here we report that Thalidezine (Tha) is a new and highly selective lysosomotropic agent (LA) with strong activity against TCL. Thalidezine diminished the acidic pH, and more importantly, induced the lysosomal membrane permeabilization (LMP). This LMP was not a passive event; it triggered the immediate and critical release of the protease Cathepsin B (CTSB) from the lysosomal lumen. We demonstrate that this cytosolic CTSB is the key executioner, directly initiating the apoptotic cascade through caspase-3 activation. Remarkably, CTSB knockdown rescued TCL cells from Tha-induced death, confirming that the CTSB-caspase axis constitutes the major death axis. Furthermore, Tha demonstrated significant in vivo efficacy in TCL cells-bearing NOD/SCID mice. In conclusion our results reveal Thalidezine a novel potent drug candidate and and uncover a defined mechanism-lysosome weaponization to release CTSB-as a therapeutically relevant vulnerability in TCL.

Keywords: CTSB; LMP; Lysosome; Lysosomotropic agent; TCL; Thalidezine

DOI: https://doi.org/10.1016/j.cbi.2026.111932

J Neurochem. 2026 Jan;170(1): e70357

Prosaposin Is Cleaved Into Saposins by Multiple Cathepsins in a Progranulin-Regulated Fashion.

Molly Hodul, Courtney Lane-Donovan, Emily S Cheang, Vienna Gao, Paul J Sampognaro, Edwina A Mambou, Zoe Yang, Aimee W Kao.

Prosaposin (PSAP) is a lysosomal protein that plays a key role in sphingolipid metabolism. PSAP is cleaved into four bioactive disulfide-rich saposins (SapA, SapB, SapC, and SapD) that catalyze sphingolipidases to promote sphingolipid breakdown. Maintaining optimal levels of PSAP and saposins is crucial for proper lysosomal function and sphingolipid homeostasis, and PSAP dysfunction is associated with juvenile-onset lysosomal storage disorders and age-associated neurodegenerative disorders. Despite this, the mechanism by which saposins are released from PSAP, and thus available to modulate sphingolipidases, sphingolipid homeostasis, and downstream lysosomal function, is not well understood. Here, we performed a comprehensive study to identify lysosomal enzymes that regulated prosaposin cleavage into saposins. In vitro cleavage assays identified multiple enzymes that could process human prosaposin into multi- and single-saposin fragments. We confirmed the role of cathepsins D and B in PSAP processing and identified several additional lysosomal proteases (cathepsins E, K, L, S, V, G, and asparagine-specific endopeptidase) that were able to process PSAP in distinctive, pH-dependent manners. In addition, we found that PGRN and multi-granulin fragments (MGFs) directly regulated the cleavage of PSAP by cathepsin D. With this study, we have shown that multiple cathepsins, PGRN, and MGFs work in concert to produce saposins under different conditions, which could present novel opportunities to modulate saposin levels in disease.

Keywords: cathepsins; lipid metabolism; lysosome; progranulin; prosaposin; proteolytic enzyme; sphingolipid

DOI: https://doi.org/10.1111/jnc.70357