Ketogenic diet reshapes cancer metabolism through lysine β-hydroxybutyrylation.

Lysine β-hydroxybutyrylation (Kbhb) is a post-translational modification induced by the ketogenic diet (KD), a diet showing therapeutic effects on multiple human diseases. Little is known how cellular processes are regulated by Kbhb. Here we show that protein Kbhb is strongly affected by the KD through a multi-omics analysis of mouse livers.

The WDR11 complex is a receptor for acidic-cluster-containing cargo proteins.

Vesicle trafficking is a fundamental process that allows for the sorting and transport of specific proteins (i.e., "cargoes") to different compartments of eukaryotic cells.

Consensus statement on extracellular vesicles in liquid biopsy for advancing laboratory medicine.

Extracellular vesicles (EVs) represent a diverse class of nanoscale membrane vesicles actively released by cells. These EVs can be further subdivided into categories like exosomes and microvesicles, based on their origins, sizes, and physical attributes. Significantly, disease-derived EVs have been detected in virtually all types of body fluids, providing a comprehensive molecular profile of their cellular origins.

Interaction between the gut microbiota and colonic enteroendocrine cells regulates host metabolism.

Nutrient handling is an essential function of the gastrointestinal tract. Hormonal responses of small intestinal enteroendocrine cells (EECs) have been extensively studied but much less is known about the role of colonic EECs in metabolic regulation. To address this core question, we investigated a mouse model deficient in colonic EECs.

TRIM25 predominately associates with anti-viral stress granules.

Stress granules (SGs) are induced by various environmental stressors, resulting in their compositional and functional heterogeneity. SGs play a crucial role in the antiviral process, owing to their potent translational repressive effects and ability to trigger signal transduction; however, it is poorly understood how these antiviral SGs differ from SGs induced by other environmental stressors. Here we identify that TRIM25, a known driver of the ubiquitination-dependent antiviral innate immune response, is a potent and critical marker of the antiviral SGs.

TBC1D23 mediates Golgi-specific LKB1 signaling.

Liver kinase B1 (LKB1), an evolutionarily conserved serine/threonine kinase, is a master regulator of the AMPK subfamily and controls cellular events such as polarity, proliferation, and energy homeostasis. Functions and mechanisms of the LKB1-AMPK axis at specific subcellular compartments, such as lysosome and mitochondria, have been established. AMPK is known to be activated at the Golgi; however, functions and regulatory mechanisms of the LKB1-AMPK axis at the Golgi apparatus remain elusive.

Human peri-gastruloids: a significant advancement in embryology research.

The peri-gastruloids comprise both embryonic (epiblast) and extraembryonic (hypoblast) tissues, faithfully mirroring crucial developmental events spanning from the immediate post-implantation phase to early organogenesis, encompassing the emergence of amniotic and yolk sac cavities, as well as the progression from bilaminar to trilaminar embryonic discs.

Nuclear transport proteins: structure, function, and disease relevance.

Proper subcellular localization is crucial for the functioning of biomacromolecules, including proteins and RNAs. Nuclear transport is a fundamental cellular process that regulates the localization of many macromolecules within the nuclear or cytoplasmic compartments. In humans, approximately 60 proteins are involved in nuclear transport, including nucleoporins that form membrane-embedded nuclear pore complexes, karyopherins that transport cargoes through these complexes, and Ran system proteins that ensure directed and rapid transport.

FAM91A1-TBC1D23 complex structure reveals human genetic variations susceptible for PCH.

Pontocerebellar hypoplasia (PCH) is a group of rare neurodevelopmental disorders with limited diagnostic and therapeutic options. Mutations in WDR11, a subunit of the FAM91A1 complex, have been found in patients with PCH-like symptoms; however, definitive evidence that the mutations are causal is still lacking. Here, we show that depletion of FAM91A1 results in developmental defects in zebrafish similar to that of TBC1D23, an established PCH gene.

Protein-level mutant p53 reporters identify druggable rare precancerous clones in noncancerous tissues.

Detecting and targeting precancerous cells in noncancerous tissues is a major challenge for cancer prevention. Massive stabilization of mutant p53 (mutp53) proteins is a cancer-specific event that could potentially mark precancerous cells, yet in vivo protein-level mutp53 reporters are lacking. Here we developed two transgenic protein-level mutp53 reporters, p53-Akaluc and p53-mCherry, that faithfully mimic the dynamics and function of mutp53 proteins in vivo.

An enteroendocrine-microbial axis in the large intestine controls host metabolism.

Nutrient handling is an essential function of the gastrointestinal tract. Most nutrient absorption occurs in the small intestine and is coordinated by hormone-producing intestinal epithelial cells known as enteroendocrine cells (EECs). In contrast, the colon mostly reclaims water and electrolytes, and handles the influx of microbially-derived metabolites, including short chain fatty acids (SCFA).

Cryo-EM structure of the Mon1-Ccz1-RMC1 complex reveals molecular basis of metazoan RAB7A activation.

Understanding of the evolution of metazoans from their unicellular ancestors is a fundamental question in biology. In contrast to fungi which utilize the Mon1-Ccz1 dimeric complex to activate the small GTPase RAB7A, metazoans rely on the Mon1-Ccz1-RMC1 trimeric complex. Here, we report a near-atomic resolution cryogenic-electron microscopy structure of the Mon1-Ccz1-RMC1 complex.

Feasibility and clinical benefits of the double-ProGlide technique for hemostasis after cryoballoon atrial fibrillation ablation with uninterrupted oral anticoagulants.

Objective: To access the efficacy and safety of the double-ProGlide technique for the femoral vein access-site closure in cryoballoon ablation with uninterrupted oral anticoagulants (OAC), and its impact on the electrophysiology laboratory time as well as hospital stay after the procedure in this observational study.

Methods: Patients with atrial fibrillation undergoing cryoballoon ablation with uninterrupted OAC at Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China from May 2019 to May 2021 were enrolled in this study. From October 2020, double-ProGlide technique was consistently used for hemostasis (ProGlide group), and before that conventional manual compression was utilized (manual compression group).

Searching for Novel Noncovalent Nuclear Export Inhibitors through a Drug Repurposing Approach.

Chromosomal region maintenance protein 1 (CRM1) is a validated anticancer drug target, and its covalent inhibitor KPT-330 has been approved for marketing. However, the development of CRM1 inhibitors, especially the noncovalent ones, is still very limited. Drug repurposing is an effective strategy to develop drug leads for new targets.

SCGN deficiency is a risk factor for autism spectrum disorder.

Autism spectrum disorder (ASD) affects 1-2% of all children and poses a great social and economic challenge for the globe. As a highly heterogeneous neurodevelopmental disorder, the development of its treatment is extremely challenging. Multiple pathways have been linked to the pathogenesis of ASD, including signaling involved in synaptic function, oxytocinergic activities, immune homeostasis, chromatin modifications, and mitochondrial functions.

GTPase-activating protein TBC1D5 coordinates with retromer to constrain synaptic growth by inhibiting BMP signaling.

Formation and plasticity of neural circuits rely on precise regulation of synaptic growth. At Drosophila neuromuscular junction (NMJ), Bone Morphogenetic Protein (BMP) signaling is critical for many aspects of synapse formation and function. The evolutionarily conserved retromer complex and its associated GTPase-activating protein TBC1D5 are critical regulators of membrane trafficking and cellular signaling.

Two siblings, distinct characteristics.

In this issue of Structure, Healy et al. discovered the PDLIM family of proteins as novel interactors of the sorting nexin SNX17, determined the NMR structure of PDLIM7 with the bound SNX17 C terminus, and suggest that PDLIM proteins could represent novel regulators of endosomal trafficking together with SNX17.

Discovery and Mechanistic Study of PafA Inhibitors.

Tuberculosis is caused by the bacterium () and is ranked as the second killer infectious disease after COVID-19. Proteasome accessory factor A (PafA) is considered an attractive target because of its low sequence conservation in humans and its role in virulence. In this study, we designed a mutant of PafA that enabled large-scale purification of active PafA.

Role of Seipin in Human Diseases and Experimental Animal Models.

Seipin, a protein encoded by the Berardinelli-Seip congenital lipodystrophy type 2 () gene, is famous for its key role in the biogenesis of lipid droplets and type 2 congenital generalised lipodystrophy (CGL2). gene mutations result in genetic diseases including CGL2, progressive encephalopathy with or without lipodystrophy (also called Celia's encephalopathy), and -associated motor neuron diseases. Abnormal expression of seipin has also been found in hepatic steatosis, neurodegenerative diseases, glioblastoma stroke, cardiac hypertrophy, and other diseases.

An evolving understanding of sorting signals for endosomal retrieval.

Complex mechanisms govern the sorting of membrane (cargo) proteins at endosomes to ensure that protein localization to the post-Golgi endomembrane system is accurately maintained. Endosomal retrieval complexes mediate sorting by recognizing specific motifs and signals in the cytoplasmic domains of cargo proteins transiting through endosomes. In this review, the recent progress in understanding the molecular mechanisms of how the retromer complex, in conjunction with sorting nexin (SNX) proteins, operates in cargo recognition and sorting is discussed.