TMEM74 promotes tumor cell survival by inducing autophagy via interactions with ATG16L1 and ATG9A
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Abstract Autophagy is a highly inducible system of intracellular degradation that occurs in lysosomes or vacuoles. Transmembrane 74 (TMEM74) has been shown to induce autophagy. However, the mechanism by which TMEM74 stimulates autophagy and the impacts of TMEM74-induced autophagy on tumor cell survival remain unclear. In this study, TMEM74 was shown to increase the autophagic flux process in different tumor cell lines. Further investigations revealed that TMEM74 interacts with ATG16L1 and ATG9A. Moreover, distinctive from the common autophagy models, it is found that TMEM74-related autophagy is independent of BECN1/PI3KC3 complex and ULK1, and TMEM74 may initiate and promote autophagy directly via interactions with ATG16L1 and ATG9A responsible for the nucleation and elongation respectively. Considering the ultimate outcome of TMEM74-induced autophagy in tumor cells, TMEM74-triggered autophagy induces a pro-survival effect on tumor cells, particularly cells under metabolic stress, consistent with alteration of a series of signal pathways. Intriguingly, TMEM74 itself can be downregulated through the autophagic process, which indicates that a potential self-regulatory loop exists so as to maintain an appropriate level of autophagy, avoiding excessive autophagy to commit tumor cells to death. According to the clinical database analysis, the high expression of TMEM74 significantly shortens the surviving periods of patients in several specific cancers indicating that TMEM74 itself can be treated as an effective potential target with clinical values to prolong surviving periods of cancer patients in the future. In conclusion, our study reveals a new mechanism by which autophagy is stimulated by a novel positive modulator through a unique pathway and demonstrates a novel connection between autophagy and cell survival, which undoubtedly serves to broaden our understanding of autophagy.Keywords:
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VCP/p97 is an essential multifunctional protein implicated in a plethora of intracellular quality control systems, and abnormal function of VCP is the underlying cause of several neurodegenerative disorders. We reported that VCP regulates the levels of the macroautophagy/autophagy-inducing lipid phosphatidylinositol-3-phosphate (PtdIns3P) by modulating the activity of the BECN1 (beclin 1)-containing phosphatidylinositol 3-kinase (PtdIns3K) complex. VCP stimulates the deubiquitinase activity of ATXN3 (ataxin 3) to stabilize BECN1 protein levels and also interacts with and promotes the assembly and kinase activity of the PtdIns3K complex. Acute inhibition of VCP activity impairs autophagy induction, demonstrated by a diminished PtdIns3P production and decreased recruitment of early autophagy markers WIPI2 and ATG16L1. Thus, VCP promotes autophagosome biogenesis, in addition to its previously described role in autophagosome maturation.
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Vacuolar programmed cell death (PCD) is indispensable for plant development and is accompanied by a dramatic growth of lytic vacuoles, which gradually digest cytoplasmic content leading to self-clearance of dying cells. Our recent data demonstrate that vacuolar PCD critically requires autophagy and its upstream regulator, a caspase-fold protease metacaspase. Furthermore, both components lie downstream of the point of no return in the cell-death pathway. Here we consider the possibilities that i) autophagy could have both cytotoxic and cytoprotective roles in the vacuolar PCD, and ii) metacaspase could augment autophagic flux through targeting an as yet unknown autophagy repressor.
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Autophagy is a catabolic process used by eukaryotic cells for the degradation and recycling of cytosolic proteins and excess or defective organelles. In yeast, autophagy is primarily a response to nutrient limitation, whereas in higher eukaryotes it also plays a role in developmental processes. Due to its essentially unlimited degradative capacity, it is critical that regulatory mechanisms are in place to modulate the timing and magnitude of the autophagic response. One set of proteins that seems to function in this regard includes a complex that contains the Atg1 kinase. Aside from Atg1, the proteins in this complex participate primarily in either nonspecific autophagy or specific types of autophagy, including the cytoplasm to vacuole targeting pathway, which operates under vegetative growth conditions, and peroxisome degradation. Accordingly, these proteins are prime candidates for factors that regulate the conversion between these pathways, including the change in size of the sequestering vesicle, the most obvious morphological difference. The atg17delta mutant forms a reduced number of small autophagosomes. As a result, it is defective in peroxisome degradation and is partially defective for autophagy. Atg17 interacts with both Atg1 and Atg13, via two coiled-coil domains, and these interactions facilitate its inclusion in the Atg1 complex.
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Historically, apoptosis and necrosis have been considered the two unique and fundamental types of cell death. However, recent evidence suggests that the programmed cell death is not only confined to apoptosis because other cell autodestruction mechanisms also exist such as autophagy. This new cellular process is a dynamic and programmed mechanism that involves sequestering of both cytoplasmatic proteins and organelles within double membrane vacuoles, which are contacted and fused with lysosomes, forming the autolysosomes. The captured elements are degraded by lysosomal proteases and removed from the cell by exocytosis. Autophagy was initially described as a critical physiological event for cell surviving to stress derived from nutrient deprivation. Autophagy has also been observed in some cardiovascular pathologies, specially those linked to ischemia/reperfusion. We review here the actual knowledge on autophagy, its implications and future relevance for the cardiovascular area.
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Macroautophagy and chaperone-mediated autophagy (CMA) are the two main mammalian lysosomal proteolytic systems. In macroautophagy, double-membrane structures engulf organelles and other intracellular constituents through a highly regulated process that involves the formation of autophagic vacuoles and their fusion with lysosomes. In CMA, selected proteins are targeted through a nonvesicular pathway to a transport complex at the lysosomal membrane, through which they are threaded into the lysosomes and degraded. Autophagy is important in development, differentiation, cellular remodelling and survival during nutrient starvation. Increasing evidence suggests that autophagic dysregulation causes accumulation of abnormal proteins or damaged organelles, which is a characteristic of chronic neurodegenerative conditions, such as Parkinson disease (PD). Evidence from post-mortem material, transgenic mice, and animal and cellular models of PD suggests that both major autophagic pathways are malfunctioning. Numerous connections exist between proteins genetically linked to autosomal dominant PD, in particular α-synuclein and LRRK2, and autophagic pathways. However, proteins involved in recessive PD, such as PINK1 and Parkin (PINK2), function in the process of mitophagy, whereby damaged mitochondria are selectively engulfed by macroautophagy. This wealth of new data suggests that both autophagic pathways are potential targets for therapeutic intervention in PD and other related neurodegenerative conditions.
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Macroautophagy, often referred to as autophagy, designates the process by which portions of the cytoplasm, intracellular organelles and long-lived proteins are engulfed in double-membraned vacuoles (autophagosomes) and sent for lysosomal degradation. Basal levels of autophagy contribute to the maintenance of intracellular homoeostasis by ensuring the turnover of supernumerary, aged and/or damaged components. Under conditions of starvation, the autophagic pathway operates to supply cells with metabolic substrates, and hence represents an important pro-survival mechanism. Moreover, autophagy is required for normal development and for the protective response to intracellular pathogens. Conversely, uncontrolled autophagy is associated with a particular type of cell death (termed autophagic, or type II) that is characterized by the massive accumulation of autophagosomes. Regulators of apoptosis (e.g. Bcl-2 family members) also modulate autophagy, suggesting an intimate cross-talk between these two degradative pathways. It is still unclear whether autophagic vacuolization has a causative role in cell death or whether it represents the ultimate attempt of cells to cope with lethal stress. For a multicellular organism, autophagic cell death might well represent a pro-survival mechanism, by providing metabolic supplies during whole-body nutrient deprivation. Alternatively, type II cell death might contribute to the disposal of cell corpses when heterophagy is deficient. Here, we briefly review the roles of autophagy in cell death and its avoidance.
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Autophagy is a dynamic and self-limiting process. The amplitude and duration of this process need to be properly controlled to maintain cell homeostasis, and excessive or insufficient autophagy activity could each lead to disease states. Compared to our understanding of the molecular mechanisms of autophagy induction, little is known about how the autophagy process is turned off after its activation. We recently identified KLHL20 as a key regulator of autophagy termination. By functioning as a substrate-binding subunit of CUL3 ubiquitin ligase, KLHL20 targets the activated ULK1 and phagophore-residing PIK3C3/VPS34 and BECN1 for ubiquitination and proteasomal degradation, which in turn triggers a destabilization of their complex components ATG13 and ATG14. These hierarchical degradation events cause the exhaustion of the autophagic pool of ULK1 and PIK3C3/VPS34 complexes, thereby preventing persistent and excessive autophagy activity. Impairment of KLHL20-dependent feedback regulation of autophagy enhances cell death under prolonged starvation and aggravates muscle atrophy in diabetic mice, which highlights the pathophysiological significance of this autophagy termination mechanism in cell survival and tissue homeostasis. Modulation of this autophagy termination pathway may be effective for treating diseases associated with deregulation of autophagy activity.
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Protein Degradation
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