ROS-induced cytosolic release of PGAM5 accelerates cancer progression via MST3-YAP axis
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ABSTRACT:
PROVIDER: PRJNA1043738 | ENA |
REPOSITORIES: ENA
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Project description:ROS-induced cytosolic release of mitochondrial PGAM5 accelerates colorectal cancer progression via MST3-mediated YAP activation
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Project description:Aberrant mtROS release in response to mitochondrial stress are considered to be a major novel feature of neoplastic transformation. However, the molecular mechanisms by which mtROS contribute to CRC development have not been fully elucidated. In this study, we showed that upon sensing the mtROS signal, the mitochondrially localized phosphatase PGAM5 undergoes cleavage in the mitochondrial transmembrane domain, and then the Cleaved PGAM5 is released into the cytoplasm. Subsequently, Cleaved PGAM5 binds to the kinase MST3 in the cytoplasm to promote MST3 dephosphorylation, resulting in a decrease in MST3 activity. Importantly, MST3 inactivation failed to regulate YAP phosphorylation, leading to YAP translocation into the nucleus, consequently promoting CRC proliferation and metastasis. Collectively, our findings identified the PGAM5-MST3-YAP axis as an important molecular mechanism through which mtROS promotes CRC development.
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Project description:Aberrant mtROS release in response to mitochondrial stress are considered to be a major novel feature of neoplastic transformation. However, the molecular mechanisms by which mtROS contribute to CRC development have not been fully elucidated. In this study, we showed that upon sensing the mtROS signal, the mitochondrially localized phosphatase PGAM5 undergoes cleavage in the mitochondrial transmembrane domain, and then the Cleaved PGAM5 is released into the cytoplasm. Subsequently, Cleaved PGAM5 binds to the kinase MST3 in the cytoplasm to promote MST3 dephosphorylation, resulting in a decrease in MST3 activity. Importantly, MST3 inactivation failed to regulate YAP phosphorylation, leading to YAP translocation into the nucleus, consequently promoting CRC proliferation and metastasis. Collectively, our findings identified the PGAM5-MST3-YAP axis as an important molecular mechanism through which mtROS promotes CRC development.
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Project description:PGAM5 is a mitochondria-localized protein phosphatase. To analyze the effect on gene expression profiles by PGAM5 in iBAT, RNA-seq analysis was performed.
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Project description:Reactive oxygen species (ROS) production is a conserved immune response, primarily mediated in Arabidopsis by the respiratory burst oxidase homolog D (RBOHD), a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase associated with the plasma membrane. A rapid increase in NADPH is necessary to fuel RBOHD proteins and hence maintain ROS production. However, the molecular mechanism underlying the NADPH generation for fueling RBOHD remains unclear. In this study, we isolated a new mutant allele of flagellin-insensitive 4 (FIN4), encoding the first enzyme in de novo NAD biosynthesis. fin4 mutants show reduced NADPH levels and impaired ROS production. However, FIN4 and other genes involved in the NAD- and NADPH-generating pathways are not highly upregulated upon elicitor treatment. Therefore, we hypothesized that a cytosolic NADP-linked dehydrogenase might be post-transcriptionally activated to keep the NADPH supply close to RBOHD. RPM1-INDUCED PROTEIN KINASE (RIPK), a receptor-like cytoplasmic kinase, regulates broad-spectrum ROS signaling in plant immunity. We then isolated the proteins associated with RIPK and identified NADP-malic enzyme 2 (NADP-ME2), an NADPH-generating enzyme. Compared with wild-type plants, nadp-me2 mutants display decreased NADP-ME activity, lower NADPH levels, as well as reduced ROS production in response to immune elicitors. Furthermore, we found that RIPK can directly phosphorylate NADP-ME2 and enhance its activity in vitro. The phosphorylation of NADP-ME2 S371 residue contributes to ROS production upon immune elicitor treatment and the susceptibility to the necrotrophic bacterium, Pectobacterium carotovorum. Overall, our study suggests that RIPK activates NADP-ME2 to rapidly increase cytosolic NADPH, hence fueling RBOHD to sustain ROS production in plant immunity.
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Project description:The protection of the replication fork structure under stress conditions is essential for genome maintenance and cancer prevention. A key signaling pathway for fork protection involves TRPV2-mediated Ca2+ release from the ER, which is triggered after the generation of cytosolic DNA and the activation of cGAS/STING. The resulting CaMKK2/AMPK activation and subsequent Exo1 phosphorylation prevent aberrant fork processing, thereby ensuring genome stability. However, it remains poorly understood how the TRPV2 channel is activated by the presence of cytosolic DNA. Here we show that the TRPM8 channel-associated factor 1 (TCAF1) plays a key role in promoting TRPV2-mediated Ca2+ release under replication stress or other conditions that activate cGAS/STING. Mechanistically, TCAF1 promotes Ca2+ release by facilitating the dissociation of STING from TRPV2, thereby relieving TRPV2 repression. Consistent with this function, TCAF1 is required for fork protection, chromosomal stability and cell survival after replication stress.
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Project description:Macrophages play a critical role in the regulation of inflammation and tissue homeostasis. In addition to their vital functions for cell survival and physiology, mitochondria play a crucial role in innate immunity as a platform for the induction of inflammatory responses by regulating cell signaling and dynamics. Dynamin-related protein 1 (Drp1) plays a role in the induction of inflammatory responses and the subsequent development of various diseases. PGAM5 (phosphoglycerate mutase member 5) is a mitochondrial outer membrane phosphatase that dephosphorylates its substrate, Drp1. Previous studies showed that PGAM5 regulates the phosphorylation of Drp1 for the activation of NKT cells and T cells. However, it is not clear how PGAM5 regulates Drp1 activity for the induction of inflammation in macrophages. Here, we demonstrate that PGAM5 activity regulates the dephosphorylation of Drp1 in macrophages, leading to the induction of proinflammatory responses in macrophages. In TLR signaling, PGAM5 regulates the expression and production of inflammatory cytokines by regulating the activation of downstream signaling pathways, including the NF-kB and MAPK pathways. Upon LPS stimulation, PGAM5 interacts with Drp1 to form a complex, leading to the production of mtROS. Furthermore, PGAM5-Drp1 signaling promotes the polarization of macrophages toward a proinflammatory phenotype. Our study further demonstrates that PGAM5-Drp1 signaling promotes metabolic reprogramming by upregulating glycolysis and mitochondrial metabolism in macrophages. Altogether, PGAM5 signaling might be a link between alterations in Drp1-mediated mitochondrial dynamics and inflammatory responses in macrophages and may be a target for the treatment of inflammatory diseases.
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Project description:The mitochondrial unfolded protein response (UPRmt) safeguards mitochondria from proteotoxic damage by activating a dedicated transcriptional response in the nucleus to restore proteostasis. How the mitochondrial protein misfolding information is signalled to the nucleus as part of the human UPRmt remains unclear. Here, we showed that UPRmt signalling is carried out by the co-occurrence of two individual signals – ROS production in mitochondria and accumulation of orphan mitochondrial proteins in the cytosol. Combining proteomics and genetic approaches, we identified that mitochondrial protein misfolding caused the release of ROS into the intermembrane space (IMS), which was essential for UPRmt signalling. ROS released from mitochondria oxidized the cytosolic HSP40 protein DNAJA1 to enhance recruitment of cytosolic HSP70 to orphan mitochondrial proteins that accumulated in parallel in the cytosol due to mitochondrial import defect. This recruitment leads to the release of HSF1 from HSP70 and its subsequent translocation to the nucleus to activate transcription of UPRmt related genes. Strikingly, we found that combining ROS and the accumulation of orphan mitochondrial proteins in the cytosol was sufficient and necessary to activate the UPRmt. Our findings reveal that monitoring of ROS and orphan mitochondrial proteins in cytosol allows an elegant surveillance to control the UPRmt via HSF1 activation in human cells. These observations reveal a novel link between mitochondrial and cytosolic proteostasis and provide molecular insight into UPRmt signalling.
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