Showing papers by "Quan Chen published in 2019"
TL;DR: The results thus uncover dual functions of STING in activating the immune response and autophagy, and suggest that STING is involved in ensuring a measured innate immune response.
Abstract: STING (stimulator of interferon genes) is a central molecule that binds to cyclic dinucleotides produced by the cyclic GMP-AMP synthase (cGAS) to activate innate immunity against microbial infection. Here we report that STING harbors classic LC-3 interacting regions (LIRs) and mediates autophagy through its direct interaction with LC3. We observed that poly(dA:dT), cGAMP, and HSV-1 induced STING-dependent autophagy and degradation of STING immediately after TBK1 activation. STING induces non-canonical autophagy that is dependent on ATG5, whereas other autophagy regulators such as Beclin1, Atg9a, ULK1, and p62 are dispensable. LIR mutants of STING abolished its interaction with LC3 and its activation of autophagy. Also, mutants that abolish STING dimerization and cGAMP-binding diminished the STING-LC3 interaction and subsequent autophagy, suggesting that STING activation is indispensable for autophagy induction. Our results thus uncover dual functions of STING in activating the immune response and autophagy, and suggest that STING is involved in ensuring a measured innate immune response.
202 citations
TL;DR: A mechanistic link between mitophagic modulation of inflammatory response and tumorigenesis is described, which implies that FUNDC1‐mediated mitophagy and its related inflammatory response may represent a therapeutic target for liver cancer.
110 citations
TL;DR: The results demonstrate that dysregulated mitochondrial QC due to defective mitophagy receptor FUNDC1 links with metabolic disorders via MAPK signaling and inflammatory responses.
Abstract: There is overwhelming evidence for an association between impaired mitochondrial function and metabolic syndrome. Mitophagy, a process that selectively removes damaged mitochondria via a specialized form of autophagy, is essential for mitochondrial quality control (mitochondrial QC) and metabolic homeostasis. We thus addressed the potential role of defective mitophagy in the pathogenesis of metabolic disorders. Mice lacking Fundc1, a newly characterized mitophagy receptor, develop more severe obesity and insulin resistance when fed a high-fat diet (HFD). Ablation of Fundc1 results in defective mitophagy and impaired mitochondrial QC in vitro and in white adipose tissue (WAT). In addition, there is more pronounced WAT remodeling with more adipose tissue-associated macrophages infiltration, more M1 macrophage polarization and thus an elevated inflammatory response. Mechanistically, hyperactivation of MAPK/JNK leads to insulin insensitivity, which can be inhibited by knocking out Mapk8/Jnk1 in fundc1 KO mice. Our results demonstrate that dysregulated mitochondrial QC due to defective mitophagy receptor FUNDC1 links with metabolic disorders via MAPK signaling and inflammatory responses. Abbreviations: ATMs: adipose tissue macrophages; BAT: brown adipose tissue; BMDMs: bone marrow-derived macrophages; GOT1/AST: glutamic-oxaloacetic transaminase 1, soluble; GPT/ALT: glutamic pyruvic transaminase, soluble; HE HFD: high-fat diet; LIR: LC3-interacting region; mitochondrial QC: mitochondrial quality control; mito-ROS: mitochondrial ROS; mtDNA: mitochondrial DNA; RT-PCR: real-time-PCR; T2D: type 2 diabetes; WAT: white adipose tissue.
102 citations
TL;DR: It is suggested that human mitochondria organize cellular proteostatic response at the risk of their own malfunction and cell lethality.
Abstract: Both protein quality and mitochondrial quality are vital for the cellular activity, and impaired proteostasis and mitochondrial dysfunction are common etiologies of aging and age-related disorders. Here, we report that the mitochondrial outer membrane protein FUNDC1 interacts with the chaperone HSC70 to promote the mitochondrial translocation of unfolded cytosolic proteins for degradation by LONP1 or for formation of non-aggresomal mitochondrion-associated protein aggregates (MAPAs) upon proteasome inhibition in cultured human cells. Integrative approaches including csCLEM, Apex, and biochemical analysis reveal that MAPAs contain ubiquitinated cytosolic proteins, autophagy receptor p62, and mitochondrial proteins. MAPAs are segregated from mitochondria in a FIS1-dependent manner and can subsequently be degraded via autophagy. Although the FUNDC1/HSC70 pathway promotes the degradation of unfolded cytosolic proteins, excessive accumulation of unfolded proteins on the mitochondria prior to MAPA formation impairs mitochondrial integrity and activates AMPK, leading to cellular senescence. We suggest that human mitochondria organize cellular proteostatic response at the risk of their own malfunction and cell lethality.
63 citations
TL;DR: It is shown that the E3 ligase SIAH2 degrades NRF1 in response to hypoxia to enhance pro-tumor metabolic and environmental effects, whereasNRF1 stabilization sensitizes tumor cells to apoptosis, representing that inhibition of NRF 1 degradation is a potential therapeutic strategy against cancer.
Abstract: The interactions between tumor cells with their microenvironments, including hypoxia, acidosis and immune cells, lead to the tumor heterogeneity which promotes tumor progression. Here, we show that SIAH2-NRF1 axis remodels tumor microenvironment through regulating tumor mitochondrial function, tumor-associated macrophages (TAMs) polarization and cell death for tumor maintenance and progression. Mechanistically, low mitochondrial gene expression in breast cancers is associated with a poor clinical outcome. The hypoxia-activated E3 ligase SIAH2 spatially downregulates nuclear-encoded mitochondrial gene expression including pyruvate dehydrogenase beta via degrading NRF1 (Nuclear Respiratory Factor 1) through ubiquitination on lysine 230, resulting in enhanced Warburg effect, metabolic reprogramming and pro-tumor immune response. Dampening NRF1 degradation under hypoxia not only impairs the polarization of TAMs, but also promotes tumor cells to become more susceptible to apoptosis in a FADD-dependent fashion, resulting in secondary necrosis due to the impairment of efferocytosis. These data represent that inhibition of NRF1 degradation is a potential therapeutic strategy against cancer.
47 citations
TL;DR: This FUNDC2/AKT/BCL-xL axis signifies a balance between platelet survival and apoptosis at the single organelle level and provides new insight for platelet-related diseases as well.
Abstract: Platelets undergo apoptosis in response to a variety of stimuli in the circulation. Mitochondria in platelets are essential for their apoptosis. Specifically, pro-survival protein BCL-xL on mitochondria is the key regulator of platelet lifespan. Here we identify an outer mitochondrial membrane protein FUNDC2 for platelet survival. FUNDC2 knockout mice carrying excessively apoptotic platelets exhibit thrombocytopenia in response to hypoxia. Mechanistically, FUNDC2 binds the lipid PIP3 via its unique, highly conserved N-terminal motif. FUNDC2 deficiency abrogates the phosphorylation of AKT and its substrate BAD in a PIP3/PI3K-dependent manner, which suppresses BCL-xL. Indeed, FUNDC2 deficiency shortens the platelet lifespan under stress. Thus, this FUNDC2/AKT/BCL-xL axis signifies a balance between platelet survival and apoptosis at the single organelle level and provides new insight for platelet-related diseases as well.
30 citations
TL;DR: Interestingly, loss of Nix increases the life span of platelets in vivo, likely through preventing autophagic degradation of the mitochondrial protein Bcl-xL, and this work suggests that targeting platelet mitophagy Nix might provide new antithrombotic strategies.
23 citations
TL;DR: FUNDC2 positively regulates platelet functions via AKT/GSK-3β/cGMP signaling pathways, which provides new insight for platelet-related diseases.
Abstract: Aims AKT kinase is vital for regulating signal transduction in platelet aggregation. We previously found that mitochondrial protein FUNDC2 mediates phosphoinositide 3-kinase (PI3K)/phosphatidylinositol-3,4,5-trisphosphate (PIP3)-dependent AKT phosphorylation and regulates platelet apoptosis. The aim of this study was to evaluate the role of FUNDC2 in platelet activation and aggregation. Methods and results We demonstrated that FUNDC2 deficiency diminished platelet aggregation in response to a variety of agonists, including adenosine 5'-diphosphate (ADP), collagen, ristocetin/VWF, and thrombin. Consistently, in vivo assays of tail bleeding and thrombus formation showed that FUNDC2-knockout mice displayed deficiency in haemostasis and thrombosis. Mechanistically, FUNDC2 deficiency impairs the phosphorylation of AKT and downstream GSK-3β in a PI3K-dependent manner. Moreover, cGMP also plays an important role in FUNDC2/AKT-mediated platelet activation. This FUNDC2/AKT/GSK-3β/cGMP axis also regulates clot retraction of platelet-rich plasma. Conclusion FUNDC2 positively regulates platelet functions via AKT/GSK-3β/cGMP signalling pathways, which provides new insight for platelet-related diseases.
12 citations
TL;DR: It is shown that the interaction between Drp1 and MiD51 is regulated by GTP binding and depends on the polymerization ofDrp1, and that dimerization of MiD 51, relevant to residue C452, is required for mitochondrial dynamics regulation.
Abstract: Mitochondrial fission is facilitated by dynamin-related protein Drp1 and a variety of its receptors. However, the molecular mechanism of how Drp1 is recruited to the mitochondrial surface by receptors MiD49 and MiD51 remains elusive. Here, we showed that the interaction between Drp1 and MiD51 is regulated by GTP binding and depends on the polymerization of Drp1. We identified two regions on MiD51 that directly bind to Drp1, and found that dimerization of MiD51, relevant to residue C452, is required for mitochondrial dynamics regulation. Our Results have suggested a multi-faceted regulatory mechanism for the interaction between Drp1 and MiD51 that illustrates the potentially complicated and tight regulation of mitochondrial fission.
11 citations
TL;DR: Together, these results showed a shift of two obligate epiphytic ferns to be facultative in secondary forests, and underwent a downward shift in their microhabitat occupancy to lower tree trunks and understory soils in response to forest degradation.
7 citations
15 Mar 2019
TL;DR: It is suggested that mitochondria actively organize the cellular proteostatic response and that the interaction between FUNDC1 and HSC70 may represent a new link between impaired proteostasis, mitochondrial dysfunction and cellular aging.
Abstract: Mitochondria have relatively independent protein quality control systems, including their own chaperones for protein folding and AAA proteases for protein degradation. Accumulating evidence has shown that cytosolic proteins and disease-causing misfolded proteins can be translocated into mitochondria and then impinge upon their function. It is important to understand the interplay between cellular proteostasis and mitochondria, as impaired proteostasis and mitochondrial dysfunction are causally linked with aging and age-related disorders. This review highlights our recent finding showing that the outer mitochondrial membrane protein FUNDC1, a previously reported mitophagy receptor, interacts with the chaperone protein HSC70 to mediate the mitochondrial translocation of cytosolic proteasomal substrates via the TOM/TIM complex into the mitochondrial matrix where they can be degraded by LONP1 protease. Excessive accumulation of unfolded proteins within mitochondria triggers the formation of Mitochondrion-Associated Protein Aggregates (MAPAs), which are subsequently autophagically degraded in a FUNDC1-dependent manner. We suggest that mitochondria actively organize the cellular proteostatic response and that the interaction between FUNDC1 and HSC70 may represent a new link between impaired proteostasis, mitochondrial dysfunction and cellular aging.
TL;DR: The findings demonstrate acclimation of S. griffithiana to both habitats, that is, epiphytic ramet can mitigate water scarcity at some cost of a reduced photosynthetic capacity, whereas terrestrial ramets can afford to improve the light capture to a higher photosynthesis capacity without any water stresses.
Abstract: Although epiphytic habitats are more stressful and heterogeneous than terrestrial habitats, how facultative epiphytes acclimate to such contrasting environments has been poorly understood. Our study focused on the variation of functional traits between epiphytic and terrestrial individuals of Selliguea griffithiana, and provided considerable functional acclimation of this species to such contrasting environments. We sampled ramets of S. griffithiana from epiphytic and terrestrial habitats of a subtropical montane moist forest, SW China. Morphological and anatomical traits, photosynthesis, biomass and ramet density of S. griffithiana were measured and it was found that these traits differed significantly between the two habitats. Frond length, stipe length, spacer length (interramet distance), stomatal density, vein density, maximal chlorophyll fluorescence and relative chlorophyll content of fronds, and biomass per ramet were all lower in epiphytic habitat than those in terrestrial habitat, whereas frond thickness and ramet density were higher in the former. Photosynthetic light-response curves revealed a higher carbon assimilation capability of individuals in terrestrial habitat than in epiphytic habitat, whereas cumulative water loss curves showed a lower water loss rate in the latter. The findings demonstrate acclimation of S. griffithiana to both habitats, that is, epiphytic ramets can mitigate water scarcity at some cost of a reduced photosynthetic capacity, whereas terrestrial ramets can afford to improve the light capture to a higher photosynthetic capacity without any water stresses.
TL;DR: This research presents a novel probabilistic procedure that allows for direct measurement of the response of the immune system to earthquake-triggered landsliding.
Abstract: [This corrects the article DOI: 10.1371/journal.pone.0211459.].