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Lipophagy, the selective engulfment of lipid droplets (LDs) by autophagosomes for lysosomal degradation, is critical to lipid and energy homeostasis. Here we show that the lipid transfer protein ORP8 is located on LDs and mediates the encapsulation of LDs by autophagosomal membranes. This function of ORP8 is independent of its lipid transporter activity and is achieved through direct interaction with phagophore-anchored LC3/GABARAPs. Upon lipophagy induction, ORP8 has increased localization on LDs and is phosphorylated by AMPK, thereby enhancing its affinity for LC3/GABARAPs. Deletion of ORP8 or interruption of ORP8-LC3/GABARAP interaction results in accumulation of LDs and increased intracellular triglyceride. Overexpression of ORP8 alleviates LD and triglyceride deposition in the liver of ob/ob mice, and Osbpl8 -/- mice exhibit liver lipid clearance defects. Our results suggest that ORP8 is a lipophagy receptor that plays a key role in cellular lipid metabolism. [ABSTRACT FROM AUTHOR]

The cGAS‐STING pathway plays an important role in host defense by sensing pathogen DNA, inducing type I IFNs, and initiating autophagy. However, the molecular mechanism of autophagosome formation in cGAS‐STING pathway‐induced autophagy is still unclear. Here, we report that STING directly interacts with WIPI2, which is the key protein for LC3 lipidation in autophagy. Binding to WIPI2 is necessary for STING‐induced autophagosome formation but does not affect STING activation and intracellular trafficking. In addition, the specific interaction between STING and the PI3P‐binding motif of WIPI2 leads to the competition of WIPI2 binding between STING and PI3P, and mutual inhibition between STING‐induced autophagy and canonical PI3P‐dependent autophagy. Furthermore, we show that the STING‐WIPI2 interaction is required for the clearance of cytoplasmic DNA and the attenuation of cGAS‐STING signaling. Thus, the direct interaction between STING and WIPI2 enables STING to bypass the canonical upstream machinery to induce LC3 lipidation and autophagosome formation. Synopsis: STING‐induced autophagy does not depend on ULK1 complex and PIK3C3 complex. Here, we report that STING directly interacts with WIPI2 and brings WIPI2 to STING‐positive vesicles. Our results reveal a mechanism by which WIPI2 is recruited to phagophore for LC3 lipidation and phagophore expansion during STING‐induced autophagosome formation. STING brings WIPI2 to STING‐positive vesicles for autophagosome formation during STING‐induced autophagy.STING and PI3P competitively bind to WIPI2, which leads to mutual inhibition between STING‐induced autophagy and PI3P‐dependent autophagy.STING‐WIPI2 interaction is required for autophagy‐dependent clearance of cytoplasmic DNA and the attenuation of cGAS‐STING signaling. [ABSTRACT FROM AUTHOR]

The transcription factor TFEB is a major regulator of lysosomal biogenesis and autophagy. There is growing evidence that posttranslational modifications play a crucial role in regulating TFEB activity. Here, we show that lactate molecules can covalently modify TFEB, leading to its lactylation and stabilization. Mechanically, lactylation at K91 prevents TFEB from interacting with E3 ubiquitin ligase WWP2, thereby inhibiting TFEB ubiquitination and proteasome degradation, resulting in increased TFEB activity and autophagy flux. Using a specific antibody against lactylated K91, enhanced TFEB lactylation was observed in clinical human pancreatic cancer samples. Our results suggest that lactylation is a novel mode of TFEB regulation and that lactylation of TFEB may be associated with high levels of autophagy in rapidly proliferating cells, such as cancer cells., (© 2024 Huang et al.)

The biosynthesis of nanoparticles in bioreactors using microbial, plant, or animal cells is at the forefront of nanotechnology. We demonstrated for the first time that luminescent, water-soluble ZnO nanocrystals (bio-ZnO NCs) can be spontaneously biosynthesized in the mammalian blood circulation, not in cells, when animals were fed with Zn(CH 3 COO) 2 aqueous solution. Serum albumin, rather than metallothioneins or glutathione, proved to play the pivotal role in biosynthesis. The bio-ZnO NCs were gradually taken up in the liver and degraded and excreted in the urine. Thus, we propose that in mammals such as rodents, bovinae, and humans, excess metal ions absorbed into the cardiovascular system via the intestine can be transformed into nanoparticles by binding to serum albumin, forming a "provisional metal-pool", to reduce the toxicity of free metal ions at high concentration and regulate metal homeostasis in the body. Furthermore, the bio-ZnO NCs, which showed favorable biocompatibility, were functionalized with the anticancer drug daunorubicin and effectively achieved controlled drug release mediated by intracellular glutathione in tumor xenograft mice.

Rapid diagnosis and targeted drug treatment require agents that possess multiple functions. Nanomaterials that facilitate optical imaging and direct drug delivery have shown great promise for effective cancer treatment. In this study, we first modified near-infrared fluorescent indium phosphide quantum dots (InP QDs) with a vascular endothelial growth factor receptor 2 (VEGFR2) monoclonal antibody to afford targeted drug delivery function. Then, a miR-92a inhibitor, an antisense microRNA that enhances the expression of tumor suppressor p63, was attached to the VEGFR2-InP QDs via electrostatic interactions. The functionalized InP nanocomposite (IMAN) selectively targets tumor sites and allows for infrared imaging in vivo. We further explored the mechanism of this active targeting. The IMAN was endocytosed and delivered in the form of microvesicles via VEGFR2-CD63 signaling. Moreover, the IMAN induced apoptosis of human myelogenous leukemia cells through the p63 pathway in vitro and in vivo. These results indicate that the IMAN may provide a new and promising chemotherapy strategy against cancer cells, particularly by its active targeting function and utility in noninvasive three-dimensional tumor imaging.

Wogonin (5,7-dihydroxy-8-methoxyflavone) is one of the active components of flavonoids isolated from Scutellariae radix and possesses antitumor effect against leukemia. Cadmium-telluride quantum dots (CdTe-QDs) are a kind of nanoparticles with great potential in functioning as an efficient drug delivery vector in biomedical research. In this study, we investigated the synergistic effect of CdTe-QDs with Wogonin on the induction of apoptosis using drug-resistant human leukemia KA cells. Flow cytometry analysis, assay of morphology under electron microscope, quantitative analysis of tumor volume and micro-CT imaging demonstrated that compared with that by pure CdTe-QDs or wogonin, the apoptosis rate increased sharply when treated wirh CdTe-QDs together with wogonin on KA cells. These results proved that the nanocomposites readily overcame the barrier of drug-resistance and provoked cell apoptosis in vitro and in vivo by facilitating the interaction between wogonin and KA cells. As known to all, it is an inevitable tendency that new effective therapies will take the place of conventional chemotherapy and radiotherapy presenting significant disadvantages. According to this article, CdTe-QD combined with wogonin is a possible alternative for some cancer treatments.