Micropeptide hSPAR regulates glutamine levels and suppresses mammary tumor growth via a TRIM21-P27KIP1-mTOR axis.

mTOR plays a pivotal role in cancer growth control upon amino acid response. Recently, CDK inhibitor P27KIP1 has been reported as a noncanonical inhibitor of mTOR signaling in MEFs, via unclear mechanisms. Here, we find that P27KIP1 degradation via E3 ligase TRIM21 is inhibited by human micropeptide hSPAR through its C-terminus (hSPAR-C), causing P27KIP1's cytoplasmic accumulation in breast cancer cells.

Optogenetic manipulation of lysosomal physiology and autophagic activity.

Lysosomes are essential degradative organelles and signaling hubs within cells, playing a crucial role in the regulation of macroautophagy/autophagy. Dysfunction of lysosomes and impaired autophagy are closely associated with the development of various neurodegenerative diseases. Enhancing lysosomal activity and boosting autophagy levels holds great promise as effective strategies for treating these diseases.

Endolysosomal channel TMEM175 mediates antitoxin activity of DABMA.

DABMA is a chemical molecule optimized from the parent compound ABMA and exhibits broad-spectrum antipathogenic activity by modulating the host's endolysosomal and autophagic pathways. Both DABMA and ABMA inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a cellular assay, which further expands their anti-pathogen spectrum in vitro. However, their precise mechanism of action has not yet been resolved.

Inhibition of lysosomal TRPML1 channel eliminates breast cancer stem cells by triggering ferroptosis.

Cancer stem cells (CSCs) are a sub-population of cells possessing high tumorigenic potential, which contribute to therapeutic resistance, metastasis and recurrence. Eradication of CSCs is widely recognized as a crucial factor in improving patient prognosis, yet the effective targeting of these cells remains a major challenge. Here, we show that the lysosomal cation channel TRPML1 represents a promising target for CSCs.

Optogenetic manipulation of lysosomal physiology and autophagy-dependent clearance of amyloid beta.

Lysosomes are degradation centers of cells and intracellular hubs of signal transduction, nutrient sensing, and autophagy regulation. Dysfunction of lysosomes contributes to a variety of diseases, such as lysosomal storage diseases (LSDs) and neurodegeneration, but the mechanisms are not well understood. Altering lysosomal activity and examining its impact on the occurrence and development of disease is an important strategy for studying lysosome-related diseases.

Bile acids modified by the intestinal microbiota promote colorectal cancer growth by suppressing CD8 T cell effector functions.

Concentrations of the secondary bile acid, deoxycholic acid (DCA), are aberrantly elevated in colorectal cancer (CRC) patients, but the consequences remain poorly understood. Here, we screened a library of gut microbiota-derived metabolites and identified DCA as a negative regulator for CD8 T cell effector function. Mechanistically, DCA suppressed CD8 T cell responses by targeting plasma membrane Ca ATPase (PMCA) to inhibit Ca-nuclear factor of activated T cells (NFAT)2 signaling.

Carnosine regulation of intracellular pH homeostasis promotes lysosome-dependent tumor immunoevasion.

Tumor cells and surrounding immune cells undergo metabolic reprogramming, leading to an acidic tumor microenvironment. However, it is unclear how tumor cells adapt to this acidic stress during tumor progression. Here we show that carnosine, a mobile buffering metabolite that accumulates under hypoxia in tumor cells, regulates intracellular pH homeostasis and drives lysosome-dependent tumor immune evasion.

Reduced lysosomal density in neuronal dendrites mediates deficits in synaptic plasticity in Huntington's disease.

Huntington's disease (HD) usually causes cognitive disorders, including learning difficulties, that emerge before motor symptoms. Mutations related to lysosomal trafficking are linked to the pathogenesis of neurological diseases, whereas the cellular mechanisms remain elusive. Here, we discover a reduction in the dendritic density of lysosomes in the hippocampus that correlates with deficits in synaptic plasticity and spatial learning in early CAG-140 HD model mice.

In vivo labeling and quantitative imaging of neuronal populations using MRI.

The study of neural circuits, which underlies perception, cognition, emotion, and behavior, is essential for understanding the mammalian brain, a complex organ consisting of billions of neurons. To study the structure and function of the brain, in vivo neuronal labeling and imaging techniques are crucial as they provide true physiological information that ex vivo methods cannot offer. In this paper, we present a new strategy for in vivo neuronal labeling and quantification using MRI.

Lysosomal Ion Channels: What Are They Good For and Are They Druggable Targets?

Lysosomes play fundamental roles in material digestion, cellular clearance, recycling, exocytosis, wound repair, Ca signaling, nutrient signaling, and gene expression regulation. The organelle also serves as a hub for important signaling networks involving the mTOR and AKT kinases. Electrophysiological recording and molecular and structural studies in the past decade have uncovered several unique lysosomal ion channels and transporters, including TPCs, TMEM175, TRPMLs, CLN7, and CLC-7.

Lysosomal K channel TMEM175 promotes apoptosis and aggravates symptoms of Parkinson's disease.

Lysosomes are degradative organelles and play vital roles in a variety of cellular processes. Ion channels on the lysosomal membrane are key regulators of lysosomal function. TMEM175 has been identified as a lysosomal potassium channel, but its modulation and physiological functions remain unclear.

Structure of the Arabidopsis guard cell anion channel SLAC1 suggests activation mechanism by phosphorylation.

Stomata play a critical role in the regulation of gas exchange and photosynthesis in plants. Stomatal closure participates in multiple stress responses, and is regulated by a complex network including abscisic acid (ABA) signaling and ion-flux-induced turgor changes. The slow-type anion channel SLAC1 has been identified to be a central controller of stomatal closure and phosphoactivated by several kinases.

CLN7 is an organellar chloride channel regulating lysosomal function.

Neuronal ceroid lipofuscinoses (NCLs) are a group of autosomal recessive lysosomal storage diseases. One variant form of late-infantile NCL (vLINCL) is caused by mutations of a lysosomal membrane protein CLN7, the function of which has remained unknown. Here, we identified CLN7 as a novel endolysosomal chloride channel.

is one of the candidate genes that play essential roles in the elongation of the seahorse prehensile tail.

Unlabelled: Seahorses are a hallmark of specialized morphological features due to their elongated prehensile tail. However, the underlying genomic grounds of seahorse tail development remain elusive. Herein, we evaluated the roles of essential genes from the gene family for the tail developmental process in the lined seahorse ().

Metabolomic profiling of single enlarged lysosomes.

Lysosomes are critical for cellular metabolism and are heterogeneously involved in various cellular processes. The ability to measure lysosomal metabolic heterogeneity is essential for understanding their physiological roles. We therefore built a single-lysosome mass spectrometry (SLMS) platform integrating lysosomal patch-clamp recording and induced nano-electrospray ionization (nanoESI)/mass spectrometry (MS) that enables concurrent metabolic and electrophysiological profiling of individual enlarged lysosomes.

A growth-factor-activated lysosomal K channel regulates Parkinson's pathology.

Lysosomes have fundamental physiological roles and have previously been implicated in Parkinson's disease. However, how extracellular growth factors communicate with intracellular organelles to control lysosomal function is not well understood. Here we report a lysosomal K channel complex that is activated by growth factors and gated by protein kinase B (AKT) that we term lysoK.

Sphingosine kinase 2 inhibitor ABC294640 suppresses neuronal excitability and inhibits multiple endogenously and exogenously expressed voltage-gated ion channels in cultured cells.

Sphingolipids regulate multiple cellular processes, including proliferation, autophagy, and apoptosis. Sphingosine kinases, the key enzymes in the metabolism of sphingolipids, are overexpressed in many cancers, making them important targets for the development of antitumor drugs. ABC294640 is a selective sphingosine kinase 2 (SK2) inhibitor that shows good antitumor activity in vitro.

Patch-clamp technique to characterize ion channels in enlarged individual endolysosomes.

According to proteomics analyses, more than 70 different ion channels and transporters are harbored in membranes of intracellular compartments such as endosomes and lysosomes. Malfunctioning of these channels has been implicated in human diseases such as lysosomal storage disorders, neurodegenerative diseases and metabolic pathologies, as well as in the progression of certain infectious diseases. As a consequence, these channels have engendered very high interest as future drug targets.

Biallelic Mutations in UNC80 Cause Persistent Hypotonia, Encephalopathy, Growth Retardation, and Severe Intellectual Disability.

Ion channel proteins are required for both the establishment of resting membrane potentials and the generation of action potentials. Hundreds of mutations in genes encoding voltage-gated ion channels responsible for action potential generation have been found to cause severe neurological diseases. In contrast, the roles of voltage-independent "leak" channels, important for the establishment and maintenance of resting membrane potentials upon which action potentials are generated, are not well established in human disease.

Structure of the voltage-gated two-pore channel TPC1 from Arabidopsis thaliana.

Two-pore channels (TPCs) contain two copies of a Shaker-like six-transmembrane (6-TM) domain in each subunit and are ubiquitously expressed in both animals and plants as organellar cation channels. Here we present the crystal structure of a vacuolar two-pore channel from Arabidopsis thaliana, AtTPC1, which functions as a homodimer. AtTPC1 activation requires both voltage and cytosolic Ca(2+).

TMEM175 Is an Organelle K(+) Channel Regulating Lysosomal Function.

Potassium is the most abundant ion to face both plasma and organelle membranes. Extensive research over the past seven decades has characterized how K(+) permeates the plasma membrane to control fundamental processes such as secretion, neuronal communication, and heartbeat. However, how K(+) permeates organelles such as lysosomes and endosomes is unknown.

A non-inactivating high-voltage-activated two-pore Na⁺ channel that supports ultra-long action potentials and membrane bistability.

Action potentials (APs) are fundamental cellular electrical signals. The genesis of short APs lasting milliseconds is well understood. Ultra-long APs (ulAPs) lasting seconds to minutes also occur in eukaryotic organisms, but their biological functions and mechanisms of generation are largely unknown.