bims-nocaut 2023-12-03 papers

Issue of 2023–12–03
three papers selected by
Quentin Frenger, University of Strasbourg

ACS Chem Neurosci. 2023 Nov 28.

Neuroinflammation-Modulating Agent SB1617 Enhances LC3-Associated Phagocytosis to Mitigate Tau Pathology.

Hana Cho, Bo Young Choi, Young-Hee Shin, Sang Won Suh, Seung Bum Park.

Tau protein aggregation and propagation in neurons and surrounding microglia are well-known risk factors for neurodegenerative diseases. Therefore, emerging therapeutic strategies that target neuroinflammatory activity in microglia have the potential to prevent tauopathy. Here, we explored the microglia-mediated neuroprotective function of SB1617 against tau aggregation. Our study revealed that SB1617-inactivated pathogenic M1-like microglia, reduced the secretion of pro-inflammatory cytokines via translational regulation, and induced microglial polarization toward the M2 phenotype and phagocytic function. Furthermore, we observed that extracellular pathogenic tau aggregates were eliminated via LC3-associated phagocytosis. The in vivo efficacy of SB1617 was confirmed in mice with traumatic brain injury in which SB1617 exerted neuroprotective effects by reducing pathogenic tau levels through microglia-mediated anti-inflammatory activity. Our results indicated that SB1617-mediated microglial surveillance with LC3-associated phagocytosis is a critical molecular mechanism in the regulation of tau proteostasis. This study provides new insights into tauopathies and directions for developing novel therapies for neurodegenerative diseases.

Keywords: LC3-associated phagocytosis; microglial polarization; neuroinflammation; proteostasis; tau pathology; traumatic brain injury

DOI: https://doi.org/10.1021/acschemneuro.3c00508

Autophagy. 2023 Nov 27. 1-3

Communication between small cytosolic dsDNA and autophagy inhibits CGAS (cyclic GMP-AMP synthase) activation.

Yu-Wei Luo, Hongyu Ji, Ai-Long Huang, Kai-Fu Tang.

The CGAS (cyclic GMP-AMP synthase)-STING1 (stimulator of interferon response cGAMP interactor 1) pathway is an important innate immune pathway that induces proinflammatory cytokine production following stimulation with dsDNA > 45 bp. We recently identified a class of ~ 20-40 bp small cytosolic dsDNA (scDNA) that blocks CGAS-STING1 activation. In this punctum, we discuss the mechanism underlying the inhibition of CGAS-STING1 activation via scDNA. scDNA binds to CGAS but cannot activate its enzymatic activity. It competes with dsDNA > 45 bp for binding with CGAS to inhibit CGAS-STING1 activation. Moreover, scDNA activates macroautophagy/autophagy and induces the autophagic degradation of STING1 and long dsDNA. Autophagy then increases scDNA levels, driving a feedback loop that accelerates the degradation of STING1 and long cytosolic dsDNA. These findings reveal that mutual communication between scDNA and autophagy inhibits CGAS-STING1 activation following stimulation with dsDNA > 45 bp.

Keywords: DNA damage; PIK3C3; STING1; interferon-β; small cytosolic double-stranded DNA

DOI: https://doi.org/10.1080/15548627.2023.2285612

Microbiol Spectr. 2023 Nov 29. e0099523

hsdSA regulated extracellular vesicle-associated PLY to protect Streptococcus pneumoniae from macrophage killing via LAPosomes.

Liping Wang, Mengyuan Liu, Yixin Qi, Jian Wang, Qixue Shi, Xiaolin Xie, Changlin Zhou, Lingman Ma.

IMPORTANCE: S. pneumoniae is a major human pathogen that undergoes a spontaneous and reversible phase variation that allows it to survive in different host environments. Interestingly, we found hsdSA, a gene that manipulated the phase variation, promoted the survival and replication of S. pneumoniae in macrophages by regulating EV production and EV-associated PLY. More importantly, here we provided the first evidence that higher EV-associated PLY (produced by D39) could form LAPosomes that were single membrane compartments containing S. pneumoniae, which are induced by integrin β1/NOX2/ROS pathway. At the same time, EV-associated PLY increased the permeability of lysosome membrane and induced an insufficient acidification to escape the host killing, and ultimately prolonged the survival of S. pneumoniae in macrophages. In contrast, lower EV-associated PLY (produced by D39ΔhsdSA) activated ULK1 recruitment to form double-layered autophagosomes to eliminate bacteria.

Keywords: LAPosomes; PLY; Streptococcus pneumoniae; extracellular vesicles; hsdSA

DOI: https://doi.org/10.1128/spectrum.00995-23