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For the sake of energy preservation, bacteria, upon transition to stationary phase, tone down their protein synthesis. This process is favored by the reversible binding of small stress-induced proteins to the ribosome to prevent unnecessary translation. One example is the conserved bacterial ribosome silencing factor (RsfS) that binds to uL14 protein onto the large ribosomal subunit and prevents its association with the small subunit. Here we describe the binding mode of Staphylococcus aureus RsfS to the large ribosomal subunit and present a 3.2 Å resolution cryo-EM reconstruction of the 50S-RsfS complex together with the crystal structure of uL14-RsfS complex solved at 2.3 Å resolution. The understanding of the detailed landscape of RsfS-uL14 interactions within the ribosome shed light on the mechanism of ribosome shutdown in the human pathogen S. aureus and might deliver a novel target for pharmacological drug development and treatment of bacterial infections. Upon transition to stationary phase or upon stress, bacteria limit protein synthesis through small inhibitory proteins that bind the ribosome. Here the authors decipher the interaction mode of the bacterial ribosome silencing factor (RsfS) at atomic details to provide an in depth view of how it shutdowns ribosomes.

Patients with mutations in Cldn16 suffer from familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) which can lead to renal insufficiency. Mice lacking claudin-16 show hypomagnesemia and hypercalciuria, but no nephrocalcinosis. Calcium oxalate and calcium phosphate are the most common insoluble calcium salts that accumulate in the kidney in the case of nephrocalcinosis, however, the formation of these salts is less favored in acidic conditions. Therefore, urine acidification has been suggested to limit the formation of calcium deposits in the kidney. Assuming that urine acidification is causative for the absence of nephrocalcinosis in the claudin-16-deficient mouse model, we aimed to alkalinize the urine of these mice by the ablation of the subunit B1 of the vesicular ATPase in addition to claudin-16. In spite of an increased urinary pH in mice lacking claudin-16 and the B1 subunit, nephrocalcinosis did not develop. Thus, urinary acidification is not the only factor preventing nephrocalcinosis in claudin-16 deficient mice.

The Bile Acid TGR5 receptor is well known to active the cAMP pathways leading to CFTR activation and Cl- ions secretion, needed for bile alkalinization and hydration. However, during cystic fibrosis development, only 10 to 15% of the patients present liver defect due to bile duct disorders, meaning that another process should compensate for the loss of CFTR activity. Interestingly, TGR5 stimulation has also been reported to mobilize Ca2+ ions. Using normal human cholangiocytes and cholangiocarcinoma cell lines, we confirmed by using a specific agonist, that TGR5 stimulation induced a Ca2+ release from the endoplasmic reticulum and an influx of extracellular Ca2+ ions. Next, this Ca2+ mobilization allows an ATP (and UTP) release, leading to the activation of P2Y receptors, reinforcing this Ca2+ mobilization. This study shows that activation of the BA receptor TGR5 has the capacity to induce the two main intracellular pathways, cAMP and IP3-Ca2+ in cholangiocytes. From our data, we speculate that the pathway we described will allow activation of the Ca2+-activated Cl- channels TMEM16A, in parallel to CFTR in non-CF cells, or to compensate in part or in totality the loss of CFTR in CF patients.Competing Interest StatementThe authors have declared no competing interest.

Distal renal tubular acidosis (dRTA) is a rare kidney disorder characterized by impaired urinary acidification due to defective proton secretion in type A intercalated cells of the collecting duct. Recently, pathogenic variants in the human gene encoding the WD Repeat Domain 72 protein (WDR72) have been reported in patients with dRTA, yet the physiological role of WDR72 in the kidney remains unknown. To elucidate the renal function of Wdr72, we generated a kidney-specific knockout mouse model (Wdr72fl/fl;Pax8-Cre+) and assessed acid–base homeostasis under baseline, acute, and chronic acid loading. Wdr72fl/fl;Pax8-Cre+ mice displayed persistently elevated urinary pH, reduced titratable acid and net acid excretion under basal and acid-loaded conditions, consistent with incomplete dRTA. While the systemic pH remained unchanged compared to controls under standard diet, chronic acid load led to mild hyperchloremic, hypokalemic metabolic acidosis. Notably, urinary NH₄⁺ excretion was increased upon acid loading accompanied by upregulation of key ammoniagenesis enzymes, which was detected even under basal conditions, consistent with a compensatory activation of proximal tubular acid excretion pathways. The total and membranous abundance of the V-ATPase B1 subunit decreased markedly within the kidney, despite unchanged transcript levels, suggesting a defect in V-ATPase trafficking or assembly. In addition, morphometric analyses revealed an increased proportion of type A intercalating cells that failed to expand upon acid loading, indicating defective adaptive plasticity. Kidney-specific Wdr72 deletion impairs distal urinary acidification through reduced V-ATPase abundance and membranous targeting, altered intercalated cell morphology, and limited adaptive remodeling, resulting in incomplete dRTA. Upregulation of renal ammoniagenesis partially compensates the acidification defect. These findings highlight WDR72 as a key regulator of distal nephron acid–base homeostasis and offer mechanistic insight into WDR72-associated dRTA. Kidney-specific deletion of Wdr72 reduced Atp6v1b1 membranous localization in intercalated cells. Kidney-specific Wdr72 knockout altered intercalated cell morphology, and limited their adaptive remodeling. The lack of the renal Wdr72 resulted in incomplete dRTA, compensated partially by elevated ammoniagenesis.