Stress-primed secretory autophagy promotes extracellular BDNF maturation by enhancing MMP9 secretion.
Ontology highlight
ABSTRACT:
SUBMITTER: Martinelli S
PROVIDER: S-EPMC8324795 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Stress response is a fundamental mechanism to maintain a healthy homeostasis and its disruption is implicated in several psychiatric disorders. Autophagy is one of the mechanisms regulating homeostasis, and it is known to be activated by cellular stressors such as starvation. In a previous study, we revealed that glucocorticoid (GC)-mediated stress also activates macroautophagy via the stress-responsive co-chaperone FK506-binding protein 51 (FKBP51). In this study we reveal that GC-mediated stress enhances secretory autophagy, a recently described Atg-dependent secretory pathway, via FKBP51. Strikingly we detected the matrix metallopeptidase 9 (Mmp9) as one of the stress-induced secreted proteins. Furthermore we found that enhanced Mmp9 secretion increases both in vitro and in vivo the cleavage of pro-brain derived neurotrophic factor (proBdnf) to its mature form (mBdnf), a key protein in neuroplasticity. This unravelled mechanism can represent a link between stress and the development of psychiatric disorders.
2021-08-25 | PXD017328 | Pride
Project description:Stress response is a fundamental mechanism to maintain a healthy homeostasis and its disruption is implicated in several psychiatric disorders. Autophagy is one of the mechanisms regulating homeostasis, and it is known to be activated by cellular stressors such as starvation. In a previous study, we revealed that glucocorticoid (GC)-mediated stress also activates macroautophagy via the stress-responsive co-chaperone FK506-binding protein 51 (FKBP51). In this study we reveal that GC-mediated stress enhances secretory autophagy, a recently described Atg-dependent secretory pathway, via FKBP51. Strikingly we detected the matrix metallopeptidase 9 (Mmp9) as one of the stress-induced secreted proteins. Furthermore we found that enhanced Mmp9 secretion increases both in vitro and in vivo the cleavage of pro-brain derived neurotrophic factor (proBdnf) to its mature form (mBdnf), a key protein in neuroplasticity. This unravelled mechanism can represent a link between stress and the development of psychiatric disorders.
2021-08-05 | PXD017076 | Pride
Project description:MicroRNA dysregulation is a hallmark of hepatocellular carcinoma (HCC), leading to tumor growth and metastasis. Previous screening on patient specimens identified miR-198 as the most downregulated miRNA in HCC. Here, we show that miR-198 compensation leads to self-release into extracellular vesicles (EVs). Importantly, the vesicular secretion is mediated by autophagy-related pathway, initiated by sequestration of p62/miR-198 complexes in autophagosome-associated vesicle fractions. miR-198 is selectively recognized and loaded by p62 into autophagosomal fractions, whereas mutated miR-198 forms neither induce autophagy and nor interact with p62. Gain and loss of function experiments, using a CRIPR/Cas knockout (KO) and transgenic site-specific p62 mutants, identified p62 as an essential repressor of cellular miR-198 abundancy. Notably, EVs, harboring miR-198/p62 protein complexes, can be uptaken by cells in the close vicinity, leading to change of gene expression in recipient cells. In conclusion, miR-198 enhances autophagy; conversely autophagic protein p62 reduces the miR-198 levels by sorting into extracellular space. miR-198 is at first transcribed as primary miRNA, after being processed into single stranded mature miR-198 form, it is transported into cytoplasm ①. By interaction with p62 protein, miR-198 conglomerates and forms a binding complex ②. Since LC3 protein is an interaction partner of p62 protein, hence miR-198 is included into autophagosomes ③. By fusion with multivesicular bodies (MVB), miR-198-binding complex was recruited into amphisomes ④, the latter of which quickly turns into secretory MVB containing intraluminal vesicles⑤. By fusion with cell membrane, intraluminal vesicles were released into extracellular space as EVs ⑥.
| S-EPMC9515045 | biostudies-literature
Project description:Increasing evidence suggests an essential function for autophagy in unconventional protein secretion (UPS). However, despite its relevance for the secretion of aggregate-prone proteins, the mechanisms of secretory autophagy in neurons have remained elusive. Here we show that the lower motoneuron disease-associated protein Plekhg5 drives the UPS of Sod1. Mechanistically, Sod1 is sequestered into the intermembrane space of autophagosomes which fuse with secretory lysosomal-related organelles (LROs). Deletion of Plekhg5 in mice disrupts the secretion of these LROs causing Sod1 accumulation at swollen presynaptic sites. A reduced secretion of toxic ALS-linked SOD1G93A following deletion of Plekhg5 in SOD1G93A mice accelerated disease onset while prolonging survival due to an attenuated microglia activation. Using human isogenic iPSC-derived motoneurons we show an impaired secretion of ALS-linked SOD1D90A, which coincided with a reduced PLEKHG5 expression. Our findings highlight an unexpected pathophysiological mechanism that converges two motoneuron disease-associated proteins into a common pathway.
2024-08-28 | GSE269588 | GEO
Project description:Nuclear protein HMGB1 is secreted in response to various stimuli and functions as a danger-associated molecular pattern. Extracellular HMGB1 induces inflammation, cytokine production, and immune cell recruitment via activation of various receptors. As HMGB1 does not contain an endoplasmic reticulum-targeting signal peptide, HMGB1 is secreted via the endoplasmic reticulum-Golgi independently via an unconventional secretion pathway. However, the mechanism underlying HMGB1 secretion remains largely unknown. Here, we investigated the role of secretory autophagy machinery and vesicular trafficking in HMGB1 secretion. We observed that HSP90AA1 (heat shock protein 90 alpha family class A member 1), a stress-inducible protein, regulates the translocation of HMGB1 from the nucleus to the cytoplasm and its secretion through direct interaction. Additionally, geldanamycin, an HSP90AA1 inhibitor, reduced HMGB1 secretion. GORASP2/GRASP55 (golgi reassembly stacking protein 2), ARF1Q71L (ADP ribosylation factor 1), and SAR1AT39N (secretion associated Ras related GTPase 1A), which promoted unconventional protein secretion, increased HMGB1 secretion. HMGB1 secretion was inhibited by an early autophagy inhibitor and diminished in ATG5-deficient cells even when GORASP2 was overexpressed. In contrast, a late autophagy inhibitor increased HMGB1 secretion under the same conditions. The multivesicular body formation inhibitor GW4869 dramatically decreased HMGB1 secretion under HMGB1 secretion-inducing conditions. Thus, we demonstrated that secretory autophagy and multivesicular body formation mediate HMGB1 secretion.
| S-EPMC8496717 | biostudies-literature
Project description:Autophagy controls the quality and quantity of the eukaryotic cytoplasm while performing two evolutionarily highly conserved functions: cell-autonomous provision of energy and nutrients by cytosol autodigestion during starvation, and removal of defunct organelles and large aggregates exceeding the capacity of other cellular degradative systems. In contrast to these autodigestive processes, autophagy in yeast has additional, biogenesis functions. However, no equivalent biosynthetic roles have been described for autophagy in mammals. Here, we show that in mammalian cells, autophagy has a hitherto unappreciated positive contribution to the biogenesis and secretion of the proinflammatory cytokine IL-1β via an export pathway that depends on Atg5, inflammasome, at least one of the two mammalian Golgi reassembly stacking protein (GRASP) paralogues, GRASP55 (GORASP2) and Rab8a. This process, which is a type of unconventional secretion, expands the functional manifestations of autophagy beyond autodigestive and quality control roles in mammals. It enables a subset of cytosolic proteins devoid of signal peptide sequences, and thus unable to access the conventional pathway through the ER, to enter an autophagy-based secretory pathway facilitating their exit from the cytoplasm.
| S-EPMC3243609 | biostudies-literature
Project description:Regulated secretion is a fundamental cellular process in which biologically active molecules stored in long-lasting secretory granules (SGs) are secreted in response to external stimuli. Many studies have described mechanisms responsible for biogenesis and secretion of SGs, but how SGs mature remains poorly understood. In a genetic screen, we discovered a large number of endolysosomal trafficking genes required for proper SG maturation, indicating that maturation of SGs might occur in a manner similar to lysosome-related organelles (LROs). CD63, a tetraspanin known to decorate LROs, also decorates SG membranes and facilitates SG maturation. Moreover, CD63-mediated SG maturation requires type II phosphatidylinositol 4 kinase (PI4KII)-dependent early endosomal sorting and accumulation of phosphatidylinositol 4-phosphate (PI4P) on SG membranes. In addition, the PI4P effector Past1 is needed for formation of stable PI4KII-containing endosomal tubules associated with this process. Our results reveal that maturation of post-Golgi-derived SGs requires trafficking via the endosomal system, similar to mechanisms employed by LROs.
| S-EPMC7055004 | biostudies-literature
Project description:Extracellular vesicles (EVs) are emerging as novel mediators of cellular communication, in part via the delivery of their contents including microRNAs; small non-coding RNAs that regulate gene expression and are crucial for neuronal circuit formation and function. Whether microRNAs are transferred between differentiated neurons is so far unknown. Moreover, the physiological role of EVs in inter-neuronal signaling is largely elusive. We observed that EVs derived from brain-derived neurotrophic factor (BDNF)-treated neurons induced dendrite complexity, synapse maturation and neuronal firing in recipient hippocampal neurons. This was dependent on the activity of three microRNAs, miR-132-5p, miR-218-5p and miR-690, that were specifically up-regulated in BDNF-induced EVs. Transcriptomic analysis further showed the differential expression of genes related to synaptogenesis in BDNF-EV-treated neurons, many of which are conserved targets of these miRNAs. Overall, this work demonstrates a novel mechanism of inter-neuronal communication, which may be highly relevant in neurological disorders characterized by aberrant BDNF signaling.
2023-12-05 | GSE184945 | GEO
Project description:Due to the hypoxia and nutrient deficiency microenvironment, malignant glioma exhibits high autophagy activity and autophagy plays a significant role in the occurrence and development of glioma. However, the potential molecular mechanism of autophagy in glioma remains unknown. In this study, we demonstrated that Golgi phosphorylation protein 3 (GOLPH3), a highly conserved protein basically concentrates in the trans-Golgi network, promoted glioma autophagy. Inhibiting autophagy by using chloroquine suppressed the stimulating effect of GOLPH3 on glioma malignant development both in vitro and in vivo. Mechanistically, GOLPH3 interacted with and recruited prohibitin-2 (PHB2), an autophagy receptor of mitochondrion, and LC3-II. PHB2 promoted cell autophagy and down-regulation of PHB2 abolished the effect of GOLPH3 on autophagy. On the side, the relative mRNA and protein levels of GOLPH3 and PHB2 were positively associated with each other and both also correlated with autophagy in glioma tissues. Together, our results revealed that GOLPH3 promotes glioma progression by enhancing PHB2-mediated autophagy and inhibiting autophagy may benefit glioma patients with GOLPH3 high level. The novel GOLPH3-PHB2-autophagy axis maybe a potential and prospective therapeutic target for gliomas.
| S-EPMC8167689 | biostudies-literature
Project description:PARK7/DJ-1 is a Parkinson disease- and cancer-associated protein that functions as a multifunctional protein involved in gene transcription regulation and anti-oxidative defense. Although PARK7 lacks the secretory signal sequence, it is secreted and plays important physiological and pathophysiological roles. Whereas secretory proteins that lack the endoplasmic reticulum-targeting signal sequence are secreted from cells by way of what is called the unconventional secretion mechanism, the specific processes responsible for causing PARK7 to be secreted across the plasma membrane have remained unclear. In the present study, we found that PARK7 secretion was increased by treatment with 6-OHDA via the unconventional secretory pathway in human neuroblastoma SH-SY5Y cells and MEF cells. We also found that 6-OHDA-induced PARK7 secretion was suppressed in Atg5-, Atg9-, or Atg16l1-deficient MEF cells or ATG16L1 knockdown SH-SY5Y cells, indicating that the autophagy-based unconventional secretory pathway is involved in PARK7 secretion. We moreover observed that 6-OHDA-derived electrophilic quinone induced oxidative stress as indicated by a decrease in glutathione levels, and that this was suppressed by pretreatment with antioxidant NAC. We further found that NAC treatment suppressed autophagy and PARK7 secretion. We also observed that 6-OHDA-induced autophagy was associated with activation of AMPK and ULK1 via a pathway which was independent of MTOR. Collectively these results suggest that electrophilic 6-OHDA quinone enhances oxidative stress, and that this is followed by AMPK-ULK1 pathway activation and induction of secretory autophagy to produce unconventional secretion of PARK7. ABBREVIATIONS:6-OHDA: 6-hydroxydopamine; AMPK: AMP-activated protein kinase; ATG: autophagy related; CAV1: caveolin 1; ER: endoplasmic reticulum; FN1: fibronectin 1; GSH: glutathione; IDE: insulin degrading enzyme; IL: interleukin; LDH: lactate dehydrogenase; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MEF: mouse embryonic fibroblast; MTOR: mechanistic target of rapamycin kinase; NAC: N-acetyl-L-cysteine; PARK7/DJ-1: Parkinsonism associated deglycase; PD: Parkinson disease; RPS6KB1/p70S6K: ribosomal protein S6 kinase B1; RPN1: ribophorin I; ROS: reactive oxygen species; ULK1: unc-51 like autophagy activating kinase 1; WT: wild-type.
| S-EPMC6152502 | biostudies-literature