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Structural data on the protein CASTOR1 reveal how the mTORC1 pathway senses intracellular arginine, suggesting a repurposing of an evolutionarily pre-metazoan mechanism. Structure of human CASTOR1 bound to arginine The mTOR pathway is a major regulator of cell growth and is deregulated in numerous diseases. It is influenced by various environmental inputs such as amino acids and growth factors. Availability of arginine can be relayed to mTORC1 through the protein CASTOR1 that interacts with the regulator GATOR2. Here, David Sabatini and colleagues present a crystal structure of arginine bound to CASTOR1. The structure and accompanying biochemistry reveal how arginine is specifically sensed by CASTOR1 and disrupts the interaction of CASTOR1 with GATOR2, triggering activation of mTORC1. CASTOR1 is structurally homologous to the lysine-binding domain of prokaryotic aspartate kinases. These results therefore establish a structural basis for arginine sensing by the mTORC1 pathway and provide insights into the evolution of a mammalian nutrient sensor. The mechanistic Target of Rapamycin Complex 1 (mTORC1) is a major regulator of eukaryotic growth that coordinates anabolic and catabolic cellular processes with inputs such as growth factors and nutrients, including amino acids 1 , 2 , 3 . In mammals arginine is particularly important, promoting diverse physiological effects such as immune cell activation, insulin secretion, and muscle growth, largely mediated through activation of mTORC1 (refs 4 , 5 , 6 , 7 ).Arginine activates mTORC1 upstream of the Rag family of GTPases 8 , through either the lysosomal amino acid transporter SLC38A9 or the GATOR2-interacting C ellular A rginine S ensor for m TOR C1 (CASTOR1) 9 , 10 , 11 , 12 . However, the mechanism by which the mTORC1 pathway detects and transmits this arginine signal has been elusive. Here, we present the 1.8 Å crystal structure of arginine-bound CASTOR1. Homodimeric CASTOR1 binds arginine at the interface of two A spartate kinase, C horismate mutase, T yrA (ACT) domains, enabling allosteric control of the adjacent GATOR2-binding site to trigger dissociation from GATOR2 and downstream activation of mTORC1. Our data reveal that CASTOR1 shares substantial structural homology with the lysine-binding regulatory domain of prokaryotic aspartate kinases, suggesting that the mTORC1 pathway exploited an ancient, amino-acid-dependent allosteric mechanism to acquire arginine sensitivity. Together, these results establish a structural basis for arginine sensing by the mTORC1 pathway and provide insights into the evolution of a mammalian nutrient sensor.

Reactive oxygen species (ROS)-mediated oxidative stress and DNA damage have recently been recognized as contributing to the efficacy of most bactericidal antibiotics, irrespective of their primary macromolecular targets. Inhibitors of targets involved in both combating oxidative stress as well as being required for in vivo survival may exhibit powerful synergistic action. This study demonstrates that the de novo arginine biosynthetic pathway in Mycobacterium tuberculosis (Mtb) is up-regulated in the early response to the oxidative stress-elevating agent isoniazid or vitamin C. Arginine deprivation rapidly sterilizes the Mtb de novo arginine biosynthesis pathway mutants ΔargB and ΔargF without the emergence of suppressor mutants in vitro as well as in vivo. Transcriptomic and flow cytometry studies of arginine-deprived Mtb have indicated accumulation of ROS and extensive DNA damage. Metabolomics studies following arginine deprivation have revealed that these cells experienced depletion of antioxidant thiols and accumulation of the upstream metabolite substrate of ArgB or ArgF enzymes. ΔargB and ΔargF were unable to scavenge host arginine and were quickly cleared from both immunocompetent and immunocompromised mice. In summary, our investigation revealed in vivo essentiality of the de novo arginine biosynthesis pathway for Mtb and a promising drug target space for combating tuberculosis.

Enteric pathogens are exposed to a dynamic polymicrobial environment in the gastrointestinal tract 1 . This microbial community has been shown to be important during infection, but there are few examples illustrating how microbial interactions can influence the virulence of invading pathogens 2 . Here we show that expansion of a group of antibiotic-resistant, opportunistic pathogens in the gut—the enterococci—enhances the fitness and pathogenesis of Clostridioides difficile . Through a parallel process of nutrient restriction and cross-feeding, enterococci shape the metabolic environment in the gut and reprogramme C. difficile metabolism. Enterococci provide fermentable amino acids, including leucine and ornithine, which increase C. difficile fitness in the antibiotic-perturbed gut. Parallel depletion of arginine by enterococci through arginine catabolism provides a metabolic cue for C. difficile that facilitates increased virulence. We find evidence of microbial interaction between these two pathogenic organisms in multiple mouse models of infection and patients infected with C. difficile . These findings provide mechanistic insights into the role of pathogenic microbiota in the susceptibility to and the severity of C. difficile infection. Enterococci enhance the fitness and pathogenesis of Clostridioides difficile in the gut by altering the amino acid composition and providing signals that increase its virulence towards the host.

There is a need to develop effective therapies for pancreatic ductal adenocarcinoma (PDA), a highly lethal malignancy with increasing incidence 1 and poor prognosis 2 . Although targeting tumour metabolism has been the focus of intense investigation for more than a decade, tumour metabolic plasticity and high risk of toxicity have limited this anticancer strategy 3 , 4 . Here we use genetic and pharmacological approaches in human and mouse in vitro and in vivo models to show that PDA has a distinct dependence on de novo ornithine synthesis from glutamine. We find that this process, which is mediated through ornithine aminotransferase (OAT), supports polyamine synthesis and is required for tumour growth. This directional OAT activity is usually largely restricted to infancy and contrasts with the reliance of most adult normal tissues and other cancer types on arginine-derived ornithine for polyamine synthesis 5 , 6 . This dependency associates with arginine depletion in the PDA tumour microenvironment and is driven by mutant KRAS. Activated KRAS induces the expression of OAT and polyamine synthesis enzymes, leading to alterations in the transcriptome and open chromatin landscape in PDA tumour cells. The distinct dependence of PDA, but not normal tissue, on OAT-mediated de novo ornithine synthesis provides an attractive therapeutic window for treating patients with pancreatic cancer with minimal toxicity. 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.

Background This review article discusses a case of sodium imbalance and fluid dysregulation in a patient with traumatic brain injury (TBI), progressing through phases including mannitol-induced osmotic diuresis, arginine vasopressin deficiency (central diabetes insipidus), and syndrome of inappropriate antidiuresis (SIAD), before eventual resolution with euvolemia. The timeline of clinical interventions, laboratory trends, and diagnostic insights highlights the complexity of managing sodium and fluid balance in TBI patients. Objective To illustrate the diagnostic and management challenges of a pediatric TBI case complicated by the sequential development of osmotic diuresis, arginine vasopressin deficiency, syndrome of inappropriate antidiuretic hormone secretion (SIAD), and subsequent stabilization. Methods We present a detailed case report of a child with severe TBI who experienced multiple phases of sodium and fluid dysregulation, necessitating vigilant monitoring and dynamic management adjustments. Results The patient initially developed profound polyuria due to mannitol-induced osmotic diuresis, which obscured the emerging arginine vasopressin deficiency. The transition to SIAD further complicated management, requiring careful fluid and sodium correction. This case underscores the importance of close monitoring in post-TBI patients to detect evolving endocrine disturbances that necessitate timely interventions. Conclusion The sequential manifestation of osmotic diuresis, arginine vasopressin deficiency, SIAD, and eventual stabilization in a single patient is a rare and complex occurrence. This case emphasizes the need for dynamic fluid and electrolyte management, with ongoing assessment to tailor interventions appropriately. Our findings highlight the critical role of multidisciplinary teams in optimizing patient outcomes in pediatric TBI cases.

Background Arginine vasopressin deficiency (central diabetes insipidus) is defined as a reduction in the release of arginine vasopressin (AVP) resulting in a variable degree of polyuria. Partial empty sella refers to an enlarged sella turcica that is not completely filled by pituitary gland. It can be either primary or secondary and its manifestation ranges from asymptomatic cases to isolated posterior pituitary, isolated anterior pituitary or both anterior and posterior pituitary dysfunctions. Diabetes insipidus caused by a partially empty sella is rare. Case presentation The patient, an 18-year-old Ethiopian woman who presented with long standing headache, increased urination, increased thirst, absence of menses and weight loss. Urine and serum osmolality was done and suggested diabetes insipidus. On further workup, brain magnetic resonant imaging was done and partially empty sella was diagnosed. Conclusion Diabetes insipidus secondary to partially empty sella is uncommon. In patients presenting with headache and anterior or posterior pituitary dysfunction, empty sella should be considered, whether partial or complete.

Diabetes mellitus (DM) and arginine vasopressin deficiency (AVP‐D) are characterized by polyuria. Marfan syndrome is an autosomal dominant disorder caused by pathogenetic variants in FBN1. Here, we report a patient with type 2 diabetes mellitus, AVP‐D, and Marfan syndrome. Although the coexistence of type 2 diabetes mellitus and AVP‐D is rare, for those patients with type 2 diabetes mellitus, the existence of AVP‐D should be considered when polyuria is not in accordance with the blood glucose levels, especially for those with a low urine specific gravity. Specific symptoms or signs help to identify Marfan syndrome early, and genetic testing of the FBN1 pathogenetic variant helps to make a definitive diagnosis. For those patients with type 2 diabetes mellitus, the existence of arginine vasopressin deficiency should be considered when polyuria is not in accordance with the blood glucose levels, especially for those with a low urine specific gravity. Specific symptoms or signs help to identify Marfan syndrome early, and genetic testing of the FBN1 pathogenetic variant helps to make a definitive diagnosis.

Background Although vaccination against coronavirus disease (COVID-19) has several side effects, hypopituitarism due to hypophysitis has rarely been reported. Case presentation An 83-year-old healthy woman, who had received her fourth COVID-19 vaccine dose 2 days before admission, presented to the emergency department with difficulty moving. On examination, impaired consciousness (Glasgow Coma Scale: 14) and fever were observed. Computed tomography and magnetic resonance imaging of the head revealed swelling from the sella turcica to the suprasellar region. Her morning serum cortisol level was low (4.4 μg/dL) and adrenocorticotropic hormone level was normal (21.6 pg/mL). Central hypothyroidism was also suspected (thyroid stimulating hormone, 0.46 μIU/mL; free triiodothyronine, 1.86 pg/mL; free thyroxine, 0.48 ng/dL). Secondary adrenocortical insufficiency, growth hormone deficiency, delayed gonadotropin response, and elevated prolactin levels were also observed. After administration of prednisolone and levothyroxine, her consciousness recovered. On the 7th day of admission, the patient developed polyuria, and arginine vasopressin deficiency was diagnosed using a hypertonic saline test. On the 15th day, the posterior pituitary gland showed a loss of high signal intensity and the polyuria resolved spontaneously. On the 134th day, the corticotropin-releasing hormone loading test showed a normal response; however, the thyrotropin-releasing hormone stimulation test showed a low response. The patient’s disease course was stable with continued thyroid and adrenal corticosteroid supplementation. Conclusions Herein, we report a rare case of anterior hypopituitarism and arginine vasopressin deficiency secondary to hypophysitis following COVID-19 vaccination.

Significance Nutritional starvation therapy is under intensive investigation because it provides a potentially lower toxicity with higher specificity than conventional cancer therapy. Autophagy, often triggered by starvation, represents an energy-saving, pro-survival cellular function; however, dysregulated autophagy could also lead to cell death, a process distinct from the classic caspase-dependent apoptosis. This study shows how arginine starvation specifically kills tumor cells by a novel mechanism involving mitochondria dysfunction, reactive oxygen species generation, DNA leakage, and chromatin autophagy, where leaked DNA is captured by giant autophagosomes. These results not only provide insights into the fundamental process of metabolic stress-based cancer therapy but also uncover a new cell-death mechanism. Autophagy is the principal catabolic prosurvival pathway during nutritional starvation. However, excessive autophagy could be cytotoxic, contributing to cell death, but its mechanism remains elusive. Arginine starvation has emerged as a potential therapy for several types of cancers, owing to their tumor-selective deficiency of the arginine metabolism. We demonstrated here that arginine depletion by arginine deiminase induces a cytotoxic autophagy in argininosuccinate synthetase (ASS1)-deficient prostate cancer cells. Advanced microscopic analyses of arginine-deprived dying cells revealed a novel phenotype with giant autophagosome formation, nucleus membrane rupture, and histone-associated DNA leakage encaptured by autophagosomes, which we shall refer to as chromatin autophagy, or chromatophagy. In addition, nuclear inner membrane (lamin A/C) underwent localized rearrangement and outer membrane (NUP98) partially fused with autophagosome membrane. Further analysis showed that prolonged arginine depletion impaired mitochondrial oxidative phosphorylation function and depolarized mitochondrial membrane potential. Thus, reactive oxygen species (ROS) production significantly increased in both cytosolic and mitochondrial fractions, presumably leading to DNA damage accumulation. Addition of ROS scavenger N-acetyl cysteine or knockdown of ATG5 or BECLIN1 attenuated the chromatophagy phenotype. Our data uncover an atypical autophagy-related death pathway and suggest that mitochondrial damage is central to linking arginine starvation and chromatophagy in two distinct cellular compartments.

Severe sepsis induces a sustained immune dysfunction associated with poor clinical behavior. In particular, lymphopenia along with increased lymphocyte apoptosis and decreased lymphocyte proliferation, enhanced circulating regulatory T cells (Treg), and the emergence of myeloid-derived suppressor cells (MDSCs) have all been associated with persistent organ dysfunction, secondary infections, and late mortality. The mechanisms involved in MDSC-mediated T cell dysfunction during sepsis share some features with those described in malignancies such as arginine deprivation. We hypothesized that increasing arginine availability would restore T cell function and decrease sepsis-induced immunosuppression. Using a mouse model of sepsis based on cecal ligation and puncture and secondary pneumonia triggered by methicillin-resistant Staphylococcus aureus inoculation, we demonstrated that citrulline administration was more efficient than arginine in increasing arginine plasma levels and restoring T cell mitochondrial function and proliferation while reducing sepsis-induced Treg and MDSC expansion. Because there is no specific therapeutic strategy to restore immune function after sepsis, we believe that our study provides evidence for developing citrulline-based clinical studies in sepsis.