The vaginal and uterine microbiota play important roles in the health of the female reproductive system. However, the interactions among the microbes in these two niches and their effects on uterine health remain unclear. Here we profile the vaginal and uterine microbial samples of 145 women, and combine with deep mining of public data and animal experiments to characterize the microbial translocation in the female reproductive tract and its role in modulating uterine health. Synchronous variation and increasing convergence of the uterine and vaginal microbiome with advancing age are shown. We also find that transplanting certain strains of vaginal bacteria into the vagina of rats induces or reduces endometritis-like symptoms, and verify the damaging or protective effects of certain vaginal bacteria on endometrium. This study clarifies the interdependent relationship of vaginal bacterial translocation with uterine microecology and endometrial health, which will undoubtedly increase our understanding of female reproductive health.

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Class III PI3-kinase (PI3KC3) is essential for autophagy initiation, but whether PI3KC3 participates in other steps of autophagy remains unknown. The HOPS complex mediates the fusion of intracellular vesicles to lysosome, but how HOPS specifically tethers autophagosome to lysosome remains elusive. Here, we report Pacer (protein associated with UVRAG as autophagy enhancer) as a regulator of autophagy. Pacer localizes to autophagic structures and positively regulates autophagosome maturation. Mechanistically, Pacer antagonizes Rubicon to stimulate Vps34 kinase activity. Next, Pacer recruits PI3KC3 and HOPS complexes to the autophagosome for their site-specific activation by anchoring to the autophagosomal SNARE Stx17. Furthermore, Pacer is crucial for the degradation of hepatic lipid droplets, the suppression of Salmonella infection, and the clearance of protein aggregates. These results not only identify Pacer as a crucial multifunctional enhancer in autophagy but also uncover both the involvement of PI3KC3 and the mediators of HOPS's specific tethering activity in autophagosome maturation.

Graphical AbstractHighlights d Pacer is a regulator of hepatic autophagy and liver homeostasis d Pacer is directly phosphorylated by mTORC1 under nutrientrich conditions d Dephosphorylated Pacer is acetylated by the GSK3-TIP60 pathway d Pacer acetylation promotes autophagosome maturation and lipid metabolism SUMMARY mTORC1 and GSK3 play critical roles in early stages of (macro)autophagy, but how they regulate late steps of autophagy remains poorly understood.Here we show that mTORC1 and GSK3-TIP60 signaling converge to modulate autophagosome maturation through Pacer, an autophagy regulator that was identified in our recent study. Hepatocytespecific Pacer knockout in mice results in impaired autophagy flux, glycogen and lipid accumulation, and liver fibrosis. Under nutrient-rich conditions, mTORC1 phosphorylates Pacer at serine157 to disrupt the association of Pacer with Stx17 and the HOPS complex and thus abolishes Pacer-mediated autophagosome maturation. Importantly, dephosphorylation of Pacer under nutrient-deprived conditions promotes TIP60-mediated Pacer acetylation, which facilitates HOPS complex recruitment and is required for autophagosome maturation and lipid droplet clearance. This work not only identifies Pacer as a regulator in hepatic autophagy and liver homeostasis in vivo but also reveals a signal integration mechanism involved in late stages of autophagy and lipid metabolism.

MoS2 QDs with high quantum-yield, variable photoluminescence emission properties and good biocompatibility are studied and applied to the bio-imaging field.