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A cell-permeable peptide is constructed that is derived from a region of an essential autophagy protein called beclin 1; the peptide is a potent inducer of autophagy in mammalian cells and in vivo in mice, and is effective in the clearance of several viruses.

Cryogenic-electron microscopy is used to determine the structure of TFEB as presented to mTORC1 for phosphorylation and an explanation is found for the strong dependence of TFEB phosphorylation on FLCN and the RagC GDP state.

Shapiro, Chang, et al. identify a conserved role for the iron-binding histone demethylase KDM3B in sensing iron levels and regulating mTORC1 through transcriptional repression of key mTORC1 pathway components.

In an experimental autoimmune encephalomyelitis model in mice, a subset of astrocytes retains an epigenetically regulated memory of past inflammation, causing exacerbated inflammation upon subsequent rechallenge.

Small GTPases such as Rabs control the positioning of lysosomes. Here, the authors unveil a molecular cascade orchestrated by Arl8/DENND6A/Rab34 that regulates lysosome location, impacting autophagy.

Staphylococcus aureus is increasingly recognized as a facultative intracellular pathogen, but it is unclear whether the intracellular lifestyle is a general feature or is restricted to some isolates. Here, Rodrigues Lopes et al. profile the interaction of 191 clinical isolates with four host cell types over time, showing that almost all isolates are internalized and that a large fraction replicate and persist within host cells.

Pannexin 1 (PANX1) is a membrane channel mediating release of signaling molecules to the extracellular space. PANX1 can be activated by GPCRs. Here, the authors elucidate a non-canonical channel activation pathway by α1-adrenergic receptor that involves HDAC6- mediated lysine deacetylation of PANX1.

The long-held doctrine that an individual neuron releases only one type of small molecule neurotransmitter has been challenged in recent years. In this Progress article, Sabatini and colleagues discuss recent evidence suggesting that co-release of GABA occurs in several neuronal populations in the adult mammalian CNS and the implications of such co-release for neuronal signalling.

The aspartate aminotransaminase GOT1 is important for maintaining redox balance. Here, the authors show that inhibition of GOT1 in pancreatic cancer cells leads to cell death via ferroptosis.

Mitotic catastrophe is a regulated mechanism that responds to aberrant mitoses leading to removal of damaged cells. Here the authors reveal how replication stress induces mitotic death through pathways regulated by WAPL and telomere deprotection.

Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder caused by mutations in the TSC1 or TSC2 genes, which negatively regulate mTORC1 signalling. Here the authors selectively delete Tsc1 from dopamine neurons in mice and find impairments in striatal dopamine release that are sufficient to reduce cognitive flexibility.

Dysregulation of an mTORC1 substrate-specific mechanism leads to constitutive activation of TFEB, and promotes kidney cystogenesis and tumorigenesis in a mouse model of Birt–Hogg–Dubé syndrome.

Super enhancers are frequently involved in the dysregulation of gene expression in cancer. Here, in kidney cancer, a super enhancer is shown to drive the expression of KLF6, which alters the expression of lipid metabolism genes and promotes tumorigenesis.

Nir Hacohen, Bruce Walker, David Sabatini, Eric Lander and colleagues perform a CRISPR–Cas9-based screen for host factors that are required for HIV infection. They identify two known and three novel factors that are necessary for viral infection but that are not required for cell viability, making them potential targets for antiviral therapy.

Life-threatening vascular tumors can be associated with uncontrolled activity of the guanine nucleotide-binding protein subunit alpha (Gαq). Here, the authors develop a murine model for these tumors and show that MEK inhibition prevents formation of vascular lesions and improves survival.

Pancreatic ductal adenocarcinoma cells show a specific dependency on ornithine aminotransferase-mediated ornithine synthesis from glutamine, providing an opportunity to develop targeted therapies with minimal toxicity for this cancer.

Insufficient glucagon signalling results in hyperaminoacidemia, which drives adaptive proliferation of glucagon-producing α cells. Here the authors report that the amino acid sensitive calcium sensing receptor (CaSR) is necessary for α cell proliferation via Gq signalling during hyperaminoacidemia.

Mitochondrial complex I deficiency is frequent in congenital, neurologic and cardiovascular disease. Here the authors demonstrate that Complex I stimulates the turnover of a mitochondrial calcium channel, which becomes stabilized during Complex I deficiency, preserving energetic homeostasis.

D1- and D2-expressing striatal neurons encode separate parts of a learned reward distribution, paralleling modern approaches in machine learning.

A subpopulation of astrocytes characterized by the expression of LAMP1 and TRAIL limits inflammation in the central nervous system through a mechanism involving the microbiota-modulated expression of IFNγ in meningeal natural killer cells.

Molecular catalysts can be made more practical by anchoring them onto electrode surfaces, but such systems are less stable than standard heterogeneous electrocatalysts. Now, supramolecular hosts bound to electrode surfaces have enabled the immobilization of molecular electrocatalysts through host–guest interactions. Desorbed or degraded guest molecules can be replaced with fresh guest molecules, extending their lifetimes.

The high degree of subtype plasticity in small cell lung cancer (SCLC) poses a therapeutic challenge. Here, the authors show that the non-neuroendocrine (non-NE) subtype of SCLC is sensitive to ferroptosis while the neuroendocrine (NE) subtype is vulnerable to TRX anti-oxidant pathway inhibition, and the combination of these two treatments in SCLC circumvents non-NE/NE subtype plasticity.

Mitochondrial energy metabolism regulates proteotoxic stress tolerance, exposing a newly discovered sensitivity to the small molecule elesclomol, which induces FDX1-mediated, copper-dependent cell death.

In tumors, hundreds of genes can undergo loss of heterozygosity (LOH). Here, the authors investigate the potential for this LOH as a class of non-driver cancer vulnerabilities.

Loss of small GTPase RAC1 suppresses intestinal tumorigenesis caused by APC loss, but impacts normal intestinal homeostasis. Here, the authors provide an alternative method of reducing RAC1 activity by the combined targeting of three RAC-GEFs and show that this approach delays intestinal tumorigenesis without the detrimental effects on normal intestinal architecture.

Single-cell RNA sequencing of cells from humans with multiple sclerosis and mice with a model of the disease identifies a population of disease-promoting astrocytes in which anti-oxidant and anti-inflammatory proteins are suppressed.

METTL2 methyltransferase is responsible for 3-methylcytosine modification of arginine tRNAs in mammals. Here the authors show that DALR anticodon binding domain containing 3 (DALRD3) forms a complex with METTL2 to recognize specific arginine tRNAs and find DALRD3 mutations in patients with developmental delay and early-onset epileptic encephalopathy.

This study reports a microscopy-based screen to find microRNAs (miRNAs) that control infection by Salmonella and Shigella, showing they have different requirements. Two miRNAs decrease Shigella actin motility through N-WASP and one miRNA inhibits Salmonella by targeting TGS2, a regulator of phagolysosomal trafficking.

Systematic base-editing and computational screens identify specific cysteine residues on VPS35 in the retromer complex as key sensors that decrease mitochondrial translation in response to reactive oxygen species signals.

Pyridoxal 5’-phosphate (PLP, vitamin B6) is crucial for various metabolic processes. Here, the authors identified SLC25A38 as a key regulator of mitochondrial PLP levels using a genome-wide CRISPRi screen and organellar metabolomics, with insights into congenital sideroblastic anemia.

Although crosstalk between the phosphatidylinositol 3-kinase (PI3K) and transforming growth factor-β pathways is important, the mechanism is obscure. Here, Yu et al. show that activation of mTORC2 downstream of PI3K leads to the linker phosphorylation of Smad2/3 and their ubiquitin-dependent degradation.

Stress-induced macroautophagy is initiated by the induction of reactive oxygen species (ROS). Here Qiao et al.show that the mTOR inhibitor REDD1 in a complex with pro-oxidant protein TXNIP induces ROS formation, leading to ATG4B suppression and autophagy activation in a largely mTOR-independent manner.

An siRNA screen for genes that suppress mutant huntingtin toxicity in both mammalian cells and Drosophila identifies glutaminyl cyclase (QPCT). Newly generated small-molecule inhibitors further identify QPCT as a druggable target for Huntington′s disease.

Plasmodium berghei activates transcription factor EB by sequestering the host cell FLCN/FNIP complex to its parasitophorous vacuole membrane depending on host cell GABARAP proteins in a CASM dependent mechanism.