bims-lypmec 2023-07-30 papers

Cells. 2023 Jul 12. pii: 1835. [Epub ahead of print]12(14):

Modulation of Lysosomal Cl- Mediates Migration and Apoptosis through the TRPML1 as a Lysosomal Cl- Sensor.

Lysosomes are responsible for protein degradation and clearance in cellular recycling centers. It has been known that the lysosomal chloride level is enriched and involved in the intrinsic lysosomal function. However, the mechanism by which chloride levels can be sensed and that of the chloride-mediated lysosomal function is unknown. In this study, we verified that reduced chloride levels acutely induced lysosomal calcium release through TRPML1 and lysosomal repositioning toward the juxtanuclear region. Functionally, low chloride-induced lysosomal calcium release attenuated cellular migration. In addition, spontaneous exposure to low chloride levels dysregulated lysosomal biogenesis and subsequently induced delayed migration and promoted apoptosis. Two chloride-sensing GXXXP motifs in the TRPML1 were identified. Mutations in the GXXXP motif of TRPML1 did not affect chloride levels, and there were no changes in migratory ability. In this study, we demonstrated that the depletion of chloride induces reformation of the lysosomal calcium pool and subsequently dysregulated cancer progression, which will assist in improving therapeutic strategies for lysosomal accumulation-associated diseases or cancer cell apoptosis.

Keywords: GXXXP motif; TRPML1; calcium; chloride; lysosome

DOI: https://doi.org/10.3390/cells12141835

Sci Adv. 2023 Jul 28. 9(30): eadg1925

Lysosomal dysfunction in Down syndrome and Alzheimer mouse models is caused by v-ATPase inhibition by Tyr682-phosphorylated APP βCTF.

Eunju Im, Ying Jiang, Philip H Stavrides, Sandipkumar Darji, Hediye Erdjument-Bromage, Thomas A Neubert, Jun Yong Choi, Jerzy Wegiel, Ju-Hyun Lee, Ralph A Nixon.

Lysosome dysfunction arises early and propels Alzheimer's disease (AD). Herein, we show that amyloid precursor protein (APP), linked to early-onset AD in Down syndrome (DS), acts directly via its β-C-terminal fragment (βCTF) to disrupt lysosomal vacuolar (H+)-adenosine triphosphatase (v-ATPase) and acidification. In human DS fibroblasts, the phosphorylated 682YENPTY internalization motif of APP-βCTF binds selectively within a pocket of the v-ATPase V0a1 subunit cytoplasmic domain and competitively inhibits association of the V1 subcomplex of v-ATPase, thereby reducing its activity. Lowering APP-βCTF Tyr682 phosphorylation restores v-ATPase and lysosome function in DS fibroblasts and in vivo in brains of DS model mice. Notably, lowering APP-βCTF Tyr682 phosphorylation below normal constitutive levels boosts v-ATPase assembly and activity, suggesting that v-ATPase may also be modulated tonically by phospho-APP-βCTF. Elevated APP-βCTF Tyr682 phosphorylation in two mouse AD models similarly disrupts v-ATPase function. These findings offer previously unknown insight into the pathogenic mechanism underlying faulty lysosomes in all forms of AD.

DOI: https://doi.org/10.1126/sciadv.adg1925

Int J Mol Sci. 2023 Jul 15. pii: 11497. [Epub ahead of print]24(14):

Regulation of mTOR Signaling: Emerging Role of Cyclic Nucleotide-Dependent Protein Kinases and Implications for Cardiometabolic Disease.

Fubiao Shi, Sheila Collins.

The mechanistic target of rapamycin (mTOR) kinase is a central regulator of cell growth and metabolism. It is the catalytic subunit of two distinct large protein complexes, mTOR complex 1 (mTORC1) and mTORC2. mTOR activity is subjected to tight regulation in response to external nutrition and growth factor stimulation. As an important mechanism of signaling transduction, the 'second messenger' cyclic nucleotides including cAMP and cGMP and their associated cyclic nucleotide-dependent kinases, including protein kinase A (PKA) and protein kinase G (PKG), play essential roles in mediating the intracellular action of a variety of hormones and neurotransmitters. They have also emerged as important regulators of mTOR signaling in various physiological and disease conditions. However, the mechanism by which cAMP and cGMP regulate mTOR activity is not completely understood. In this review, we will summarize the earlier work establishing the ability of cAMP to dampen mTORC1 activation in response to insulin and growth factors and then discuss our recent findings demonstrating the regulation of mTOR signaling by the PKA- and PKG-dependent signaling pathways. This signaling framework represents a new non-canonical regulation of mTOR activity that is independent of AKT and could be a novel mechanism underpinning the action of a variety of G protein-coupled receptors that are linked to the mTOR signaling network. We will further review the implications of these signaling events in the context of cardiometabolic disease, such as obesity, non-alcoholic fatty liver disease, and cardiac remodeling. The metabolic and cardiac phenotypes of mouse models with targeted deletion of Raptor and Rictor, the two essential components for mTORC1 and mTORC2, will be summarized and discussed.

Keywords: PKA; PKG; Raptor; Rictor; cAMP; cGMP; cardiac hypertrophy; fatty liver disease; mTOR; obesity

DOI: https://doi.org/10.3390/ijms241411497