ABSTRACT
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. New data revealing the importance of different SNX proteins and detailing how post-translational modifications can modulate cargo sorting to respond to changes in the environment are highlighted along with the key role that endosomal protein sorting plays in SARS-CoV-2 infection.
ABSTRACT
Neutrophil extracellular traps (NETs) have been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS) driven by viruses or bacteria, as well as in numerous immune-mediated disorders. Histone citrullination by the enzyme peptidylarginine deiminase 4 (PAD4) and the consequent decondensation of chromatin are hallmarks in the induction of NETs. Nevertheless, additional histone modifications that may govern NETosis are largely overlooked. Herein, we show that histone deacetylases (HDACs) play critical roles in driving NET formation in human and mouse neutrophils. HDACs belonging to the zinc-dependent lysine deacetylases family are necessary to deacetylate histone H3, thus allowing the activity of PAD4 and NETosis. Of note, HDAC inhibition in mice protects against microbial-induced pneumonia and septic shock, decreasing NETosis and inflammation. Collectively, our findings illustrate a new fundamental step that governs the release of NETs and points to HDAC inhibitors as therapeutic agents that may be used to protect against ARDS and sepsis.