Phagosomal signalling of the C-type lectin receptor Dectin-1 is terminated by intramembrane proteolysis.

Sensing of pathogens by pattern recognition receptors (PRR) is critical to initiate protective host defence reactions. However, activation of the immune system has to be carefully titrated to avoid tissue damage necessitating mechanisms to control and terminate PRR signalling. Dectin-1 is a PRR for fungal ß-glucans on immune cells that is rapidly internalised after ligand-binding. Here, we demonstrate that pathogen recognition by the Dectin-1a isoform results in the formation of a stable receptor fragment devoid of the ligand binding domain. This fragment persists in phagosomal membranes and contributes to signal transduction which is terminated by the intramembrane proteases Signal Peptide Peptidase-like (SPPL) 2a and 2b. Consequently, immune cells lacking SPPL2b demonstrate increased anti-fungal ROS production, killing capacity and cytokine responses. The identified mechanism allows to uncouple the PRR signalling response from delivery of the pathogen to degradative compartments and identifies intramembrane proteases as part of a regulatory circuit to control anti-fungal immune responses.

[Metabolic acidosis]. / Metabolische Azidose.

Acid-base disorders due to different etiologies are frequently encountered in daily clinical practice and may result in life-threatening situations. Basic knowledge of the diagnostic and therapeutic approach of acid-base disorders is therefore essential for every clinician. Acid-base disorders should be treated according to their underlying etiology. Therefore, diagnosis of the underlying etiology is the critical step in the process of care for patients with acid-base disorders. Undirected buffering with HCO3 - should be avoided, since the application of HCO3 - might lead to severe side effects. A strict diagnostic pathway for the diagnosis of acid-base disorders is required, which should be vigorously applied:- analysis of the pH to classify acidemia or alkalemia- analysis of pCO2 and HCO3 - to classify the primary acid base disorder- analysis of the adequate regulation in order to detect additional acid-base disorders- analysis of the anion gap and the relationship of the anion gap vs. the change in HCO3 - to detect further metabolic disordersMetabolic acidosis can be divided into two main etiologies:- acidosis with addition of acid with increased anion gap,- acidosis with loss of HCO3 - with normal anion gap.