Epithelial Cell NOD1/IRGM Recruits STX17 to Neisseria gonorrhoeae-Containing Endosomes to Initiate Lysosomal Degradation.

Neisseria gonorrhoeae establishes tight interactions with mucosal epithelia through activity of its type IV pilus, while pilus retraction forces activate autophagic responses toward invading gonococci. Here we studied pilus-independent epithelial cell responses and showed that pilus-negative gonococci residing in early and late endosomes are detected and targeted by nucleotide-binding oligomerization domain 1 (NOD1). NOD1 subsequently forms a complex with immunity-related guanosine triphosphatase M (IRGM) and autophagy-related 16-like 1 (ATG16L1) to activate autophagy and recruit microtubule-associated protein light chain 3 (LC3) to the intracellular bacteria. IRGM furthermore directly recruits syntaxin 17 (STX17), which is able to form tethering complexes with the lysosome. Importantly, IRGM-STX17 interactions are enhanced by LC3 but were still observed at lower levels in an LC3 knockout cell line. These findings demonstrate key roles for NOD1 and IRGM in the sensing of intracellular N gonorrhoeae and subsequent directing of the bacterium to the lysosome for degradation.

Mesenchymal stromal cell-based therapy in lung diseases; from research to clinic.

Recent studies demonstrated that mesenchymal stem cells (MSCs) are important for the cell-based therapy of diseased or injured lung due to their immunomodulatory and regenerative properties as well as limited side effects in experimental animal models. Preclinical studies have shown that MSCs have also a remarkable effect on the immune cells, which play major roles in the pathogenesis of multiple lung diseases, by modulating their activity, proliferation, and functions. In addition, MSCs can inhibit both the infiltrated immune cells and detrimental immune responses in the lung and can be used in treating lung diseases caused by a virus infection such as Tuberculosis and SARS-COV-2. Moreover, MSCs are a source for alveolar epithelial cells such as type 2 (AT2) cells. These MSC-derived functional AT2-like cells can be used to treat and diminish serious lung disorders, including acute lung injury, asthma, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis in animal models. As an alternative MSC-based therapy, extracellular vesicles that are derived from MSC-derived can be employed in regenerative medicine. Herein, we discussed the key research findings from recent clinical and preclinical studies on the functions of MSCs in treating some common and well-studied lung diseases. We also discussed the mechanisms underlying MSC-based therapy of well-studied lung diseases, and the recent employment of MSCs in both the attenuation of lung injury/inflammation and promotion of the regeneration of lung alveolar cells after injury. Finally, we described the role of MSC-based therapy in treating major pulmonary diseases such as pneumonia, COPD, asthma, and idiopathic pulmonary fibrosis (IPF).

Gonococcal OMV-delivered PorB induces epithelial cell mitophagy.

The bacterial pathogen Neisseria gonorrhoeae is able to invade epithelial cells and survive intracellularly. During this process, it secretes outer membrane vesicles (OMVs), however, the mechanistic details for interactions between gonococcal OMVs and epithelial cells and their impact on intracellular survival are currently not established. Here, we show that gonococcal OMVs induce epithelial cell mitophagy to reduce mitochondrial secretion of reactive oxygen species (ROS) and enhance intracellular survival. We demonstrate that OMVs deliver PorB to mitochondria to dissipate the mitochondrial membrane potential, resulting in mitophagy induction through a conventional PINK1 and OPTN/NDP52 mechanism. Furthermore, PorB directly recruits the E3 ubiquitin ligase RNF213, which decorates PorB lysine residue 171 with K63-linked polyubiquitin to induce mitophagy in a p62-dependent manner. These results demonstrate a mechanism in which polyubiquitination of a bacterial virulence factor that targets mitochondria directs mitophagy processes to this organelle to prevent its secretion of deleterious ROS.