scholarly journals Arf6 promotes autophagosome formation via effects on phosphatidylinositol 4,5-bisphosphate and phospholipase D

2012 ◽  
Vol 196 (4) ◽  
pp. 483-496 ◽  
Author(s):  
Kevin Moreau ◽  
Brinda Ravikumar ◽  
Claudia Puri ◽  
David C. Rubinsztein
Keyword(s):  
Plasma Membrane ◽  
Phospholipase D ◽  
Indirect Effects ◽  
Mammalian Target Of Rapamycin ◽  
Ubiquitin Proteasome System ◽  
Autophagosome Formation ◽  
Positive Role ◽  
Membrane Flow ◽  
Small G Protein ◽  
Ubiquitin Proteasome

Macroautophagy (in this paper referred to as autophagy) and the ubiquitin–proteasome system are the two major catabolic systems in cells. Autophagy involves sequestration of cytosolic contents in double membrane–bounded vesicles called autophagosomes. The membrane source for autophagosomes has received much attention, and diverse sources, such as the plasma membrane, Golgi, endoplasmic reticulum, and mitochondria, have been implicated. These may not be mutually exclusive, but the exact sources and mechanism involved in the formation of autophagosomes are still unclear. In this paper, we identify a positive role for the small G protein Arf6 in autophagosome formation. The effect of Arf6 on autophagy is mediated by its role in the generation of phosphatidylinositol 4,5-bisphosphate (PIP2) and in inducing phospholipase D (PLD) activity. PIP2 and PLD may themselves promote autophagosome biogenesis by influencing endocytic uptake of plasma membrane into autophagosome precursors. However, Arf6 may also influence autophagy by indirect effects, such as either by regulating membrane flow from other compartments or by modulating PLD activity independently of the mammalian target of rapamycin.

scholarly journals Ubiquitin–proteasome system inhibitors and AMPK regulation in hepatic cold ischaemia and reperfusion injury: possible mechanisms

2012 ◽  
Vol 123 (2) ◽  
pp. 93-98 ◽  
Author(s):  
Susagna Padrissa-Altés ◽  
Mohamed Amine Zaouali ◽  
Ramon Bartrons ◽  
Joan Roselló-Catafau
Keyword(s):  
Liver Transplantation ◽  
Reperfusion Injury ◽  
Energy State ◽  
Mammalian Target Of Rapamycin ◽  
Ubiquitin Proteasome System ◽  
Protein Kinase Activity ◽  
Ischaemia Reperfusion Injury ◽  
Ubiquitin Proteasome ◽  
Preservation Solutions ◽  
Potential Strategy

In the present Hypothesis article, we summarize and present data from the literature that support our hypothesis on the potential mechanisms by which UPS (ubiquitin–proteasome system) inhibitors reduce I/R (ischaemia/reperfusion) injury in the liver. I/R is the main cause of primary liver failure and, consequently, minimizing the detrimental effects of this process could increase the number of suitable transplantation grafts and also enhance the survival rate of patients after liver transplantation. A potential strategy to reduce I/R injury is the use of UPS inhibitors either as additives to preservation solutions or as drugs administered to patients. However, there is still controversy over whether the use of UPS inhibitors is beneficial or deleterious with regard to liver injury. From our experience and the few studies that have investigated the role of UPS in hepatic I/R, we believe that the use of UPS inhibitors is a potential strategy to reduce I/R injury in liver transplantation and graft preservation. We hypothesize that one of the main mechanisms of action of UPS inhibitors may be the up-regulation of AMPK (AMP-activated protein kinase) activity and the consequent down-regulation of mTOR (mammalian target of rapamycin), which may finally influence autophagy and preserve the energy state of the cell.

scholarly journals Excessive glucocorticoid-induced muscle MuRF1 overexpression is independent of Akt/FoXO1 pathway

2017 ◽  
Vol 37 (6) ◽  
Author(s):  
Xiao Juan Wang ◽  
Jing Jing Xiao ◽  
Lei Liu ◽  
Hong Chao Jiao ◽  
Hai Lin
Keyword(s):  
Muscle Protein ◽  
Mammalian Target Of Rapamycin ◽  
Ring Finger ◽  
Ubiquitin Proteasome System ◽  
C2c12 Cells ◽  
Detectable Effect ◽  
High Concentration ◽  
Mtor Phosphorylation ◽  
Ubiquitin Proteasome

The ubiquitin-proteasome system (UPS)-dependent proteolysis plays a major role in the muscle catabolic action of glucocorticoids (GCs). Atrogin-1 and muscle-specific RING finger protein 1 (MuRF1), two E3 ubiquitin ligases, are uniquely expressed in muscle. It has been previously demonstrated that GC treatment induced MuRF1 and atrogin-1 overexpression. However, it is yet unclear whether the higher pharmacological dose of GCs induced muscle protein catabolism through MuRF1 and atrogin-1. In the present study, the role of atrogin-1 and MuRF1 in C2C12 cells protein metabolism during excessive dexamethasone (DEX) was studied. The involvement of Akt/forkhead box O1 (FoXO1) signaling pathway and the cross-talk between anabolic regulator mammalian target of rapamycin (mTOR) and catabolic regulator FoXO1 were investigated. High concentration of DEX increased MuRF1 protein level in a time-dependent fashion (P<0.05), while had no detectable effect on atrogin-1 protein (P>0.05). FoXO1/3a (Thr24/32) phosphorylation was enhanced (P<0.05), mTOR phosphorylation was suppressed (P<0.05), while Akt protein expression was not affected (P>0.05) by DEX. RU486 treatment inhibited the DEX-induced increase of FoXO1/3a phosphorylation (P<0.05) and MuRF1 protein; LY294002 (LY) did not restore the stimulative effect of DEX on the FoXO1/3a phosphorylation (P>0.05), but inhibited the activation of MuRF1 protein induced by DEX (P<0.05); rapamycin (RAPA) inhibited the stimulative effect of DEX on the FoXO1/3a phosphorylation and MuRF1 protein (P<0.05).

scholarly journals mTOR inhibition activates overall protein degradation by the ubiquitin proteasome system as well as by autophagy

2015 ◽  
Vol 112 (52) ◽  
pp. 15790-15797 ◽  
Author(s):  
Jinghui Zhao ◽  
Bo Zhai ◽  
Steven P. Gygi ◽  
Alfred Lewis Goldberg
Keyword(s):  
Amino Acids ◽  
Protein Synthesis ◽  
Protein Degradation ◽  
Mammalian Cells ◽  
Cholesterol Biosynthesis ◽  
Mammalian Target Of Rapamycin ◽  
Ubiquitin Proteasome System ◽  
Mtor Inhibition ◽  
Protein Ubiquitination ◽  
Ubiquitin Proteasome

Growth factors and nutrients enhance protein synthesis and suppress overall protein degradation by activating the protein kinase mammalian target of rapamycin (mTOR). Conversely, nutrient or serum deprivation inhibits mTOR and stimulates protein breakdown by inducing autophagy, which provides the starved cells with amino acids for protein synthesis and energy production. However, it is unclear whether proteolysis by the ubiquitin proteasome system (UPS), which catalyzes most protein degradation in mammalian cells, also increases when mTOR activity decreases. Here we show that inhibiting mTOR with rapamycin or Torin1 rapidly increases the degradation of long-lived cell proteins, but not short-lived ones, by stimulating proteolysis by proteasomes, in addition to autophagy. This enhanced proteasomal degradation required protein ubiquitination, and within 30 min after mTOR inhibition, the cellular content of K48-linked ubiquitinated proteins increased without any change in proteasome content or activity. This rapid increase in UPS-mediated proteolysis continued for many hours and resulted primarily from inhibition of mTORC1 (not mTORC2), but did not require new protein synthesis or key mTOR targets: S6Ks, 4E-BPs, or Ulks. These findings do not support the recent report that mTORC1 inhibition reduces proteolysis by suppressing proteasome expression [Zhang Y, et al. (2014) Nature 513(7518):440–443]. Several growth-related proteins were identified that were ubiquitinated and degraded more rapidly after mTOR inhibition, including HMG-CoA synthase, whose enhanced degradation probably limits cholesterol biosynthesis upon insulin deficiency. Thus, mTOR inhibition coordinately activates the UPS and autophagy, which provide essential amino acids and, together with the enhanced ubiquitination of anabolic proteins, help slow growth.

scholarly journals Clathrin-mediated endocytosis is essential for the selective degradation of maternal membrane proteins and preimplantation development

Development ◽  
2021 ◽  
Vol 148 (14) ◽  
Author(s):  
Akihito Morita ◽  
Yuhkoh Satouh ◽  
Hidetaka Kosako ◽  
Hisae Kobayashi ◽  
Akira Iwase ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Membrane Proteins ◽  
Ubiquitin Proteasome System ◽  
Maternal Plasma ◽  
Early Embryogenesis ◽  
Mouse Embryos ◽  
Cell Stage ◽  
Selective Degradation ◽  
Kinase C ◽  
Ubiquitin Proteasome

ABSTRACT Fertilization triggers significant cellular remodeling through the oocyte-to-embryo transition. In this transition, the ubiquitin-proteasome system and autophagy are essential for the degradation of maternal components; however, the significance of degradation of cell surface components remains unknown. In this study, we show that multiple maternal plasma membrane proteins, such as the glycine transporter GlyT1a, are selectively internalized from the plasma membrane to endosomes in mouse embryos by the late two-cell stage and then transported to lysosomes for degradation at the later stages. During this process, large amounts of ubiquitylated proteins accumulated on endosomes. Furthermore, the degradation of GlyT1a with mutations in potential ubiquitylation sites was delayed, suggesting that ubiquitylation may be involved in GlyT1a degradation. The clathrin inhibitor blocked GlyT1a internalization. Strikingly, the protein kinase C (PKC) activator triggered the heterochronic internalization of GlyT1a; the PKC inhibitor markedly blocked GlyT1a endocytosis. Lastly, clathrin inhibition completely blocked embryogenesis at the two-cell stage and inhibited cell division after the four-cell stage. These findings demonstrate that PKC-dependent clathrin-mediated endocytosis is essential for the selective degradation of maternal membrane proteins during oocyte-to-embryo transition and early embryogenesis.

scholarly journals IMiDs induce FAM83F degradation via an interaction with CK1α to attenuate Wnt signalling

2020 ◽  
Author(s):  
Karen Dunbar ◽  
Thomas J. Macartney ◽  
Gopal P. Sapkota
Keyword(s):  
Plasma Membrane ◽  
Protein Complexes ◽  
Ubiquitin Proteasome System ◽  
Specific Protein ◽  
Protective Role ◽  
Wnt Signalling ◽  
Target Protein ◽  
Genetic Ablation ◽  
Ubiquitin Proteasome ◽  
Canonical Wnt

ABSTRACTImmunomodulatory imide drugs (IMiDs) bind CRBN, a substrate receptor of the Cul4A E3 ligase complex, enabling neo-substrate recruitment and degradation via the ubiquitin-proteasome system. Here, we report FAM83F as such a neo-substrate. We recently showed that the eight FAM83 proteins (A-H) interact with members of the serine/threonine protein kinase CK1 family, to regulate their subcellular distribution and distinct biological roles. CK1α is a well-established IMiD neo-substrate and we demonstrate here that IMiD-induced FAM83F degradation requires its association with CK1α. Despite all FAM83 proteins interacting with CK1α, no other FAM83 protein is degraded by IMiDs. FAM83F is localised to the plasma membrane, and consistent with this, IMiD treatment results in depletion of both FAM83F and CK1α levels from the plasma membrane. We have recently identified FAM83F as a mediator of the canonical Wnt signalling pathway. The IMiD-induced degradation of FAM83F attenuated Wnt signalling in colorectal cancer cells and removed CK1α from the plasma membrane, mirroring the phenotypes observed with genetic ablation of FAM83F. Intriguingly, in many cancer cell lines, IMiD-induced degradation of CK1α is only modest and incomplete. In line with this observation, the expression of FAM83G, which also binds to CK1α, appears to attenuate the IMiD-induced degradation of CK1α, suggesting a protective role for FAM83G on CK1α. Our findings reveal that the efficiency of target protein degradation by IMiDs, and perhaps other degraders such as PROTACs, relies on the nature of the inherent multiprotein complex in which the target protein exists. Our findings unearth opportunities for developing degraders to target specific protein complexes.

scholarly journals The Role of ATG16 in Autophagy and The Ubiquitin Proteasome System

Cells ◽  
2018 ◽  
Vol 8 (1) ◽  
pp. 2 ◽  
Author(s):  
Qiuhong Xiong ◽  
Wenjing Li ◽  
Ping Li ◽  
Min Yang ◽  
Changxin Wu ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Current Knowledge ◽  
Ubiquitin Proteasome System ◽  
Degradation Pathways ◽  
Autophagosome Formation ◽  
Cell Homeostasis ◽  
Independent Functions ◽  
Ubiquitin Proteasome

Autophagy and the ubiquitin proteasome system (UPS) are the two major cellular degradation pathways, which are critical for the maintenance of cell homeostasis. The two pathways differ in their mechanisms and clients. The evolutionary conserved ATG16 plays a key role in autophagy and appears to link autophagy with the UPS. Here, we review the role of ATG16 in different species. We summarize the current knowledge of its functions in autophagosome membrane expansion and autophagosome formation, in Crohn’s disease, and in bacterial sequestration. In addition, we provide information on its autophagy-independent functions and its role in the crosstalk between autophagy and the UPS.

scholarly journals The Role of Autophagy in Chemical Proteasome Inhibition Model of Retinal Degeneration

2021 ◽  
Vol 22 (14) ◽  
pp. 7271
Author(s):  
Merry Gunawan ◽  
Choonbing Low ◽  
Kurt Neo ◽  
Siawey Yeo ◽  
Candice Ho ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Structural Integrity ◽  
Mammalian Target Of Rapamycin ◽  
Neuroblastoma Cells ◽  
Proteasome Inhibition ◽  
Ubiquitin Proteasome System ◽  
Ocular Tissue ◽  
Protective Mechanism ◽  
Ubiquitin Proteasome

We recently demonstrated that chemical proteasome inhibition induced inner retinal degeneration, supporting the pivotal roles of the ubiquitin–proteasome system in retinal structural integrity maintenance. In this study, using beclin1-heterozygous (Becn1-Het) mice with autophagic dysfunction, we tested our hypothesis that autophagy could be a compensatory retinal protective mechanism for proteasomal impairment. Despite the reduced number of autophagosome, the ocular tissue morphology and intraocular pressure were normal. Surprisingly, Becn1-Het mice experienced the same extent of retinal degeneration as was observed in wild-type mice, following an intravitreal injection of a chemical proteasome inhibitor. Similarly, these mice equally responded to other chemical insults, including endoplasmic reticulum stress inducer, N-methyl-D-aspartate, and lipopolysaccharide. Interestingly, in cultured neuroblastoma cells, we found that the mammalian target of rapamycin-independent autophagy activators, lithium chloride and rilmenidine, rescued these cells against proteasome inhibition-induced death. These results suggest that Becn1-mediated autophagy is not an effective intrinsic protective mechanism for retinal damage induced by insults, including impaired proteasomal activity; furthermore, autophagic activation beyond normal levels is required to alleviate the cytotoxic effect of proteasomal inhibition. Further studies are underway to delineate the precise roles of different forms of autophagy, and investigate the effects of their activation in rescuing retinal neurons under various pathological conditions.

scholarly journals Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies

2020 ◽  
Vol 21 (8) ◽  
pp. 3028 ◽  
Author(s):  
Fiona Limanaqi ◽  
Francesca Biagioni ◽  
Stefano Gambardella ◽  
Pietro Familiari ◽  
Alessandro Frati ◽  
...  
Keyword(s):  
Protein Misfolding ◽  
Glycogen Synthase ◽  
Mammalian Target Of Rapamycin ◽  
Ubiquitin Proteasome System ◽  
Alpha Synuclein ◽  
Fused In Sarcoma ◽  
Complex Interactions ◽  
Morphological Studies ◽  
Transcription Factor Eb ◽  
Ubiquitin Proteasome

Alterations in autophagy and the ubiquitin proteasome system (UPS) are commonly implicated in protein aggregation and toxicity which manifest in a number of neurological disorders. In fact, both UPS and autophagy alterations are bound to the aggregation, spreading and toxicity of the so-called prionoid proteins, including alpha synuclein (α-syn), amyloid-beta (Aβ), tau, huntingtin, superoxide dismutase-1 (SOD-1), TAR-DNA-binding protein of 43 kDa (TDP-43) and fused in sarcoma (FUS). Recent biochemical and morphological studies add to this scenario, focusing on the coordinated, either synergistic or compensatory, interplay that occurs between autophagy and the UPS. In fact, a number of biochemical pathways such as mammalian target of rapamycin (mTOR), transcription factor EB (TFEB), Bcl2-associated athanogene 1/3 (BAG3/1) and glycogen synthase kinase beta (GSk3β), which are widely explored as potential targets in neurodegenerative proteinopathies, operate at the crossroad between autophagy and UPS. These biochemical steps are key in orchestrating the specificity and magnitude of the two degradation systems for effective protein homeostasis, while intermingling with intracellular secretory/trafficking and inflammatory pathways. The findings discussed in the present manuscript are supposed to add novel viewpoints which may further enrich our insight on the complex interactions occurring between cell-clearing systems, protein misfolding and propagation. Discovering novel mechanisms enabling a cross-talk between the UPS and autophagy is expected to provide novel potential molecular targets in proteinopathies.

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