The Experts below are selected from a list of 34533 Experts worldwide ranked by ideXlab platform
Terje Johansen - One of the best experts on this subject based on the ideXlab platform.
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turnip mosaic virus counteracts selective autophagy of the viral silencing suppressor hcpro
Plant Physiology, 2018Co-Authors: Anders Hafren, Steingrim Svenning, Terje Johansen, Suayib Ustun, Anton Hochmuth, Daniel HofiusAbstract:Autophagy is a conserved intracellular degradation pathway and has emerged as a key mechanism of antiviral immunity in metazoans, including the selective elimination of viral components. In turn, some animal viruses are able to escape and modulate autophagy for enhanced pathogenicity. Whether host autophagic responses and viral countermeasures play similar roles in plant-virus interactions is not well understood. Here, we have identified selective autophagy as antiviral pathway during plant infection with turnip mosaic virus (TuMV), a positive-stranded RNA potyvirus. We show that the autophagy cargo receptor NBR1 suppresses viral accumulation by targeting the viral RNA silencing suppressor helper-component proteinase (HCpro), presumably in association with virus-induced RNA granules. Intriguingly, TuMV seems to antagonize NBR1-dependent autophagy during infection by the activity of distinct viral proteins, thereby limiting its antiviral capacity. We also found that NBR1-independent bulk autophagy prevents premature plant death, thus extending the lifespan of virus reservoirs and particle production. Together, our study highlights a conserved role of selective autophagy in antiviral immunity and suggests the evolvement of viral protein functions to inhibit autophagy processes, despite a potential trade-off in host survival.
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p38(MAPK)-regulated induction of p62 and NBR1 after photodynamic therapy promotes autophagic clearance of ubiquitin aggregates and reduces reactive oxygen species levels by supporting Nrf2-antioxidant signaling.
Free radical biology & medicine, 2013Co-Authors: N Rubio, Terje Johansen, Julien Verrax, Michael Dewaele, Tom Verfaillie, Jacques Piette, Patrizia AgostinisAbstract:Abstract Emerging evidence indicates that oxidative stress instigates the formation of ubiquitin (Ub) aggregates, substrates of autophagy, through a process requiring the ubiquitin binding adaptors p62/SQSTM1 and NBR1. Here, we have investigated the role of p62 and NBR1 in cell survival after hypericin-mediated photodynamic therapy (Hyp-PDT), a procedure known to incite robust reactive oxygen species (ROS)-based endoplasmic reticulum stress and autophagy pathways. We found that Hyp-PDT stimulated the formation of p62- and NBR1-associated Ub aggregates in normal and cancer cells, which were ultimately removed by autophagy, through a mechanism partially regulated by p38 MAPK . In line with this, genetic or pharmacological p38 MAPK inhibition reduced p62 and NBR1 levels and aggregate formation and impaired Nrf2 activation, thus increasing photo-oxidative stress and cell death. p62-deficient cells, or cells lacking p62 and with reduced levels of NBR1 (through siRNA knockdown), also displayed reduced aggregate formation but exhibited attenuated ROS levels, reduced caspase activation, and improved survival after Hyp-PDT. The increased resistance to photo-oxidative stress exhibited by cells lacking p62 and/or NBR1 was overruled by the inhibition of p38 MAPK , which restored cytotoxic ROS levels, thus indicating the relevance of this signal in the control of cell viability. Taken together these findings provide evidence that in photodynamically treated cells a p38 MAPK -regulated pathway coordinates the p62/NBR1-mediated clearance of cytosolic aggregates and mitigates PDT-induced proteotoxicity. They also reveal that a functional p38 MAPK –Nrf2 signal is required to keep ROS levels in check and protect against PDT-induced proteotoxicity, independent of aggregate formation.
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NBR1 acts as an autophagy receptor for peroxisomes
Journal of Cell Science, 2013Co-Authors: Elizabeth Deosaran, Trond Lamark, Yuqing Wang, Kenneth Bowitz Larsen, Graeme Sargent, Miluska Jauregui, Jennifer Lippincottschwartz, Andreas Brech, Terje JohansenAbstract:Selective macro-autophagy is an intracellular process by which large cytoplasmic materials are selectively sequestered and degraded in the lysosomes. Substrate selection is mediated by ubiquitylation and recruitment of ubiquitin-binding autophagic receptors such as p62, NBR1, NDP52 and Optineurin. Although it has been shown that these receptors act cooperatively to target some types of substrates to nascent autophagosomes, their precise roles are not well understood. We examined selective autophagic degradation of peroxisomes (pexophagy), and found that NBR1 is necessary and sufficient for pexophagy. Mutagenesis studies of NBR1 showed that the amphipathic α-helical J domain, the ubiquitin-associated (UBA) domain, the LC3-interacting region and the coiled-coil domain are necessary to mediate pexophagy. Strikingly, substrate selectivity is partly achieved by NBR1 itself by coincident binding of the J and UBA domains to peroxisomes. Although p62 is not required when NBR1 is in excess, its binding to NBR1 increases the efficiency of NBR1-mediated pexophagy. Together, these results suggest that NBR1 is the specific autophagy receptor for pexophagy.
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plant NBR1 is a selective autophagy substrate and a functional hybrid of the mammalian autophagic adapters NBR1 and p62 sqstm1
Autophagy, 2011Co-Authors: Steingrim Svenning, Kirsten Krause, Trond Lamark, Terje JohansenAbstract:(Macro)autophagy encompasses both an unselective, bulk degradation of cytoplasmic contents as well as selective autophagy of damaged organelles, intracellular microbes, protein aggregates, cellular structures and specific soluble proteins. Selective autophagy is mediated by autophagic adapters, like p62/SQSTM1 and NBR1. p62 and NBR1 are themselves selective autophagy substrates, but they also act as cargo receptors for degradation of other substrates. Surprisingly, we found that homologs of NBR1 are distributed throughout the eukaryotic kingdom, while p62 is confined to the metazoans. As a representative of all organisms having only an NBR1 homolog we studied Arabidopsis thaliana NBR1 (AtNBR1) in more detail. AtNBR1 is more similar to mammalian NBR1 than to p62 in domain architecture and amino acid sequence. However, similar to p62, AtNBR1 homo-polymerizes via the PB1 domain. Hence, AtNBR1 has hybrid properties of mammalian NBR1 and p62. AtNBR1 has 2 UBA domains, but only the C-terminal UBA domain bound u...
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plant NBR1 is a selective autophagy substrate and a functional hybrid of the mammalian autophagic adapters NBR1 and p62 sqstm1
Autophagy, 2011Co-Authors: Steingrim Svenning, Kirsten Krause, Trond Lamark, Terje JohansenAbstract:(Macro)autophagy encompasses both an unselective, bulk degradation of cytoplasmic contents as well as selective autophagy of damaged organelles, intracellular microbes, protein aggregates, cellular structures and specific soluble proteins. Selective autophagy is mediated by autophagic adapters, like p62/SQSTM1 and NBR1. p62 and NBR1 are themselves selective autophagy substrates, but they also act as cargo receptors for degradation of other substrates. Surprisingly, we found that homologs of NBR1 are distributed throughout the eukaryotic kingdom, while p62 is confined to the metazoans. As a representative of all organisms having only an NBR1 homolog we studied Arabidopsis thaliana NBR1 (AtNBR1) in more detail. AtNBR1 is more similar to mammalian NBR1 than to p62 in domain architecture and amino acid sequence. However, similar to p62, AtNBR1 homo-polymerizes via the PB1 domain. Hence, AtNBR1 has hybrid properties of mammalian NBR1 and p62. AtNBR1 has 2 UBA domains, but only the C-terminal UBA domain bound ubiquitin. AtNBR1 bound AtATG8 through a conserved LIR (LC3-interacting region) motif and required co-expression of AtATG8 or human GABARAPL2 to be recognized as an autophagic substrate in HeLa cells. To monitor the autophagic sequestration of AtNBR1 in Arabidopsis we made transgenic plants expressing AtNBR1 fused to a pH-sensitive fluorescent tag, a tandem fusion of the red, acid-insensitive mCherry and the acid-sensitive yellow fluorescent proteins. This strategy allowed us to show that AtNBR1 is an autophagy substrate degraded in the vacuole dependent on the polymerization property of the PB1 domain and of expression of AtATG7. A functional LIR was required for vacuolar import.
Trond Lamark - One of the best experts on this subject based on the ideXlab platform.
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NBR1 acts as an autophagy receptor for peroxisomes
Journal of Cell Science, 2013Co-Authors: Elizabeth Deosaran, Trond Lamark, Yuqing Wang, Kenneth Bowitz Larsen, Graeme Sargent, Miluska Jauregui, Jennifer Lippincottschwartz, Andreas Brech, Terje JohansenAbstract:Selective macro-autophagy is an intracellular process by which large cytoplasmic materials are selectively sequestered and degraded in the lysosomes. Substrate selection is mediated by ubiquitylation and recruitment of ubiquitin-binding autophagic receptors such as p62, NBR1, NDP52 and Optineurin. Although it has been shown that these receptors act cooperatively to target some types of substrates to nascent autophagosomes, their precise roles are not well understood. We examined selective autophagic degradation of peroxisomes (pexophagy), and found that NBR1 is necessary and sufficient for pexophagy. Mutagenesis studies of NBR1 showed that the amphipathic α-helical J domain, the ubiquitin-associated (UBA) domain, the LC3-interacting region and the coiled-coil domain are necessary to mediate pexophagy. Strikingly, substrate selectivity is partly achieved by NBR1 itself by coincident binding of the J and UBA domains to peroxisomes. Although p62 is not required when NBR1 is in excess, its binding to NBR1 increases the efficiency of NBR1-mediated pexophagy. Together, these results suggest that NBR1 is the specific autophagy receptor for pexophagy.
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plant NBR1 is a selective autophagy substrate and a functional hybrid of the mammalian autophagic adapters NBR1 and p62 sqstm1
Autophagy, 2011Co-Authors: Steingrim Svenning, Kirsten Krause, Trond Lamark, Terje JohansenAbstract:(Macro)autophagy encompasses both an unselective, bulk degradation of cytoplasmic contents as well as selective autophagy of damaged organelles, intracellular microbes, protein aggregates, cellular structures and specific soluble proteins. Selective autophagy is mediated by autophagic adapters, like p62/SQSTM1 and NBR1. p62 and NBR1 are themselves selective autophagy substrates, but they also act as cargo receptors for degradation of other substrates. Surprisingly, we found that homologs of NBR1 are distributed throughout the eukaryotic kingdom, while p62 is confined to the metazoans. As a representative of all organisms having only an NBR1 homolog we studied Arabidopsis thaliana NBR1 (AtNBR1) in more detail. AtNBR1 is more similar to mammalian NBR1 than to p62 in domain architecture and amino acid sequence. However, similar to p62, AtNBR1 homo-polymerizes via the PB1 domain. Hence, AtNBR1 has hybrid properties of mammalian NBR1 and p62. AtNBR1 has 2 UBA domains, but only the C-terminal UBA domain bound u...
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plant NBR1 is a selective autophagy substrate and a functional hybrid of the mammalian autophagic adapters NBR1 and p62 sqstm1
Autophagy, 2011Co-Authors: Steingrim Svenning, Kirsten Krause, Trond Lamark, Terje JohansenAbstract:(Macro)autophagy encompasses both an unselective, bulk degradation of cytoplasmic contents as well as selective autophagy of damaged organelles, intracellular microbes, protein aggregates, cellular structures and specific soluble proteins. Selective autophagy is mediated by autophagic adapters, like p62/SQSTM1 and NBR1. p62 and NBR1 are themselves selective autophagy substrates, but they also act as cargo receptors for degradation of other substrates. Surprisingly, we found that homologs of NBR1 are distributed throughout the eukaryotic kingdom, while p62 is confined to the metazoans. As a representative of all organisms having only an NBR1 homolog we studied Arabidopsis thaliana NBR1 (AtNBR1) in more detail. AtNBR1 is more similar to mammalian NBR1 than to p62 in domain architecture and amino acid sequence. However, similar to p62, AtNBR1 homo-polymerizes via the PB1 domain. Hence, AtNBR1 has hybrid properties of mammalian NBR1 and p62. AtNBR1 has 2 UBA domains, but only the C-terminal UBA domain bound ubiquitin. AtNBR1 bound AtATG8 through a conserved LIR (LC3-interacting region) motif and required co-expression of AtATG8 or human GABARAPL2 to be recognized as an autophagic substrate in HeLa cells. To monitor the autophagic sequestration of AtNBR1 in Arabidopsis we made transgenic plants expressing AtNBR1 fused to a pH-sensitive fluorescent tag, a tandem fusion of the red, acid-insensitive mCherry and the acid-sensitive yellow fluorescent proteins. This strategy allowed us to show that AtNBR1 is an autophagy substrate degraded in the vacuole dependent on the polymerization property of the PB1 domain and of expression of AtATG7. A functional LIR was required for vacuolar import.
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selective autophagy mediated by autophagic adapter proteins
Autophagy, 2011Co-Authors: Terje Johansen, Trond LamarkAbstract:Mounting evidence suggests that autophagy is a more selective process than originally anticipated. The discovery and characterization of autophagic adapters, like p62 and NBR1, has provided mechanistic insight into this process. p62 and NBR1 are both selectively degraded by autophagy and able to act as cargo receptors for degradation of ubiquitinated substrates. A direct interaction between these autophagic adapters and the autophagosomal marker protein LC3, mediated by a so-called LIR (LC3-interacting region) motif, their inherent ability to polymerize or aggregate as well as their ability to specifically recognize substrates are required for efficient selective autophagy. These three required features of autophagic cargo receptors are evolutionarily conserved and also employed in the yeast cytoplasm-to-vacuole targeting (Cvt) pathway and in the degradation of P granules in C. elegans. Here, we review the mechanistic basis of selective autophagy in mammalian cells discussing the degradation of misfolded proteins, p62 bodies, aggresomes, mitochondria and invading bacteria. The emerging picture of selective autophagy affecting the regulation of cell signaling with consequences for oxidative stress responses, tumorigenesis and innate immunity is also addressed.
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a reporter cell system to monitor autophagy based on p62 sqstm1
Autophagy, 2010Co-Authors: Kenneth Bowitz Larsen, Trond Lamark, Terje Johansen, Aud Overvatn, Ingvill Harneshaug, Geir BjorkoyAbstract:Macroautophagy (hereafter referred to as autophagy) is a catabolic pathway to isolate and transport cytosolic components to the lysosome for degradation. Recently, autophagy receptors, like p62/SQSTM1 and NBR1, which physically link autophagic cargo to ATG8/MAP1-LC3/GABARAP family members located on the forming autophagic membranes, have been identified. To identify conditions or compounds that affect autophagy, cell systems that efficiently report on autophagic flux are required. Here we describe reporter cell systems based on induced expression of GFPp62, GFP-NBR1 or GFP-LC3B. The degradation of the fusion proteins was followed after promoter shut-off by flow cytometry of live cells. All three fusion proteins were degraded at a basal rate by autophagy. Surprisingly, the basal degradation rate varied for the three reporter fusion proteins. GFP-LC3B was the most stable protein. GFP-NBR1 was most efficiently degraded under basal conditions while degradation of GFP-p62 displayed the strongest response to amino acid starvation. GFP-p62 was found to perform the best of the tested reporters. Single cell analysis of autophagic flux by flow cytometry allows estimates of heterogeneous cell populations. The feasibility of this approach was demonstrated using transient overexpression of a dominant negative ULK1 kinase and siRNA-mediated knockdown of LC3B to inhibit autophagic degradation of GFP-p62. The inducible GFP-p62 cell system allows quantification by several approaches and will be useful in screening for compounds or conditions that affect the rate of autophagy. Inducers of autophagy can be identified using rich medium whereas inhibitors are identified under starvation conditions.
Rosette Lidereau - One of the best experts on this subject based on the ideXlab platform.
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characterisation of a 161 kb deletion extending from the NBR1 to the brca1 genes in a french breast ovarian cancer family
Human Mutation, 2003Co-Authors: Sophie Gad, Ivan Bièche, Michel Barrois, Federica Casilli, Catherine Dehainault, Aaron Bensimon, Alain Aurias, Sabine Pagesberhouet, Marion Gauthiervillars, Rosette LidereauAbstract:A large germline deletion removing exons 1 to 22 of the BRCA1 gene has been previously detected using quantitative PCR based methods (QMPSF and real time PCR gene dosage assay) in a woman affected with breast and ovarian cancer. Here, we report its characterisation by using colour bar code on combed DNA of the BRCA1 region. The 5′ boundary is located in a Alu Y sequence in NBR1 intron 18 whereas the 3' boundary is located in a Alu Sc sequence in BRCA1 intron 22. This 161 kb deletion encompassing the NBR1, ΨBRCA1, NBR2 and BRCA1 genes is the largest BRCA1 deletion reported so far. No specific phenotype was associated with the hemizygosity of these four genes. © 2003 Wiley-Liss, Inc.
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characterisation of a 161 kb deletion extending from the NBR1 to the brca1 genes in a french breast ovarian cancer family
Human Mutation, 2003Co-Authors: Sophie Gad, Ivan Bièche, Michel Barrois, Federica Casilli, Catherine Dehainault, Aaron Bensimon, Alain Aurias, Sabine Pagesberhouet, Marion Gauthiervillars, Rosette LidereauAbstract:A large germline deletion removing exons 1 to 22 of the BRCA1 gene has been previously detected using quantitative PCR based methods (QMPSF and real time PCR gene dosage assay) in a woman affected with breast and ovarian cancer. Here, we report its characterisation by using colour bar code on combed DNA of the BRCA1 region. The 5' boundary is located in a Alu Y sequence in NBR1 intron 18 whereas the 3' boundary is located in a Alu Sc sequence in BRCA1 intron 22. This 161 kb deletion encompassing the NBR1, PsiBRCA1, NBR2 and BRCA1 genes is the largest BRCA1 deletion reported so far. No specific phenotype was associated with the hemizygosity of these four genes.
Jie Zhou - One of the best experts on this subject based on the ideXlab platform.
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Brassinosteroids act as a positive regulator of NBR1-dependent selective autophagy in response to chilling stress in tomato.
Journal of experimental botany, 2019Co-Authors: Cheng Chi, Pingping Fang, Xiao-jian Xia, Kai Shi, Yan-hong Zhou, Jie ZhouAbstract:Autophagy is a highly conserved and regulated catabolic process involved in the degradation of protein aggregates, which plays critical roles in eukaryotes. In plants, multiple molecular processes can induce or suppress autophagy but the mechanism of its regulation by phytohormones is poorly understood. Brassinosteroids (BRs) are steroid phytohormones that play crucial roles in plant response to stresses. Here, we investigate the role of BRs in NBR1-dependent selective autophagy in response to chilling stress in tomato. BRs and their signaling element BZR1 can induce autophagy and accumulation of the selective autophagy receptor NBR1 in tomato under chilling stress. Cold increased the stability of BZR1, which was promoted by BRs. Cold- and BR-induced increased BZR1 stability activated the transcription of several autophagy-related genes (ATGs) and NBR1 genes by directly binding to their promoters, which resulted in selective autophagy. Furthermore, silencing of these ATGs or NBR1 genes resulted in a decreased accumulation of several functional proteins and an increased accumulation of ubiquitinated proteins, subsequently compromising BR-induced cold tolerance. These results strongly suggest that BRs regulate NBR1-dependent selective autophagy in a BZR1-dependent manner in response to chilling stress in tomato.
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e3 ubiquitin ligase chip and NBR1 mediated selective autophagy protect additively against proteotoxicity in plant stress responses
PLOS Genetics, 2014Co-Authors: Jie Zhou, Yan Zhang, Yingjin Chi, Baofang Fan, Zhixiang ChenAbstract:Plant stress responses require both protective measures that reduce or restore stress-inflicted damage to cellular structures and mechanisms that efficiently remove damaged and toxic macromolecules, such as misfolded and damaged proteins. We have recently reported that NBR1, the first identified plant autophagy adaptor with a ubiquitin-association domain, plays a critical role in plant stress tolerance by targeting stress-induced, ubiquitinated protein aggregates for degradation by autophagy. Here we report a comprehensive genetic analysis of CHIP, a chaperone-associated E3 ubiquitin ligase from Arabidopsis thaliana implicated in mediating degradation of nonnative proteins by 26S proteasomes. We isolated two chip knockout mutants and discovered that they had the same phenotypes as the NBR1 mutants with compromised tolerance to heat, oxidative and salt stresses and increased accumulation of insoluble proteins under heat stress. To determine their functional interactions, we generated chip NBR1 double mutants and found them to be further compromised in stress tolerance and in clearance of stress-induced protein aggregates, indicating additive roles of CHIP and NBR1. Furthermore, stress-induced protein aggregates were still ubiquitinated in the chip mutants. Through proteomic profiling, we systemically identified heat-induced protein aggregates in the chip and NBR1 single and double mutants. These experiments revealed that highly aggregate-prone proteins such as Rubisco activase and catalases preferentially accumulated in the NBR1 mutant while a number of light-harvesting complex proteins accumulated at high levels in the chip mutant after a relatively short period of heat stress. With extended heat stress, aggregates for a large number of intracellular proteins accumulated in both chip and NBR1 mutants and, to a greater extent, in the chip NBR1 double mutant. Based on these results, we propose that CHIP and NBR1 mediate two distinct but complementary anti-proteotoxic pathways and protein's propensity to aggregate under stress conditions is one of the critical factors for pathway selection of protein degradation.
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NBR1 mediated selective autophagy targets insoluble ubiquitinated protein aggregates in plant stress responses
PLOS Genetics, 2013Co-Authors: Jie Zhou, Jian Wang, Yuan Cheng, Jingquan YuAbstract:Plant autophagy plays an important role in delaying senescence, nutrient recycling, and stress responses. Functional analysis of plant autophagy has almost exclusively focused on the proteins required for the core process of autophagosome assembly, but little is known about the proteins involved in other important processes of autophagy, including autophagy cargo recognition and sequestration. In this study, we report functional genetic analysis of Arabidopsis NBR1, a homolog of mammalian autophagy cargo adaptors P62 and NBR1. We isolated two NBR1 knockout mutants and discovered that they displayed some but not all of the phenotypes of autophagy-deficient atg5 and atg7 mutants. Like ATG5 and ATG7, NBR1 is important for plant tolerance to heat, oxidative, salt, and drought stresses. The role of NBR1 in plant tolerance to these abiotic stresses is dependent on its interaction with ATG8. Unlike ATG5 and ATG7, however, NBR1 is dispensable in age- and darkness-induced senescence and in resistance to a necrotrophic pathogen. A selective role of NBR1 in plant responses to specific abiotic stresses suggest that plant autophagy in diverse biological processes operates through multiple cargo recognition and delivery systems. The compromised heat tolerance of atg5, atg7, and NBR1 mutants was associated with increased accumulation of insoluble, detergent-resistant proteins that were highly ubiquitinated under heat stress. NBR1, which contains an ubiquitin-binding domain, also accumulated to high levels with an increasing enrichment in the insoluble protein fraction in the autophagy-deficient mutants under heat stress. These results suggest that NBR1-mediated autophagy targets ubiquitinated protein aggregates most likely derived from denatured or otherwise damaged nonnative proteins generated under stress conditions.
Masaaki Komatsu - One of the best experts on this subject based on the ideXlab platform.
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NBR1-mediated p62-liquid droplets enhance the Keap1-Nrf2 system.
EMBO reports, 2020Co-Authors: Pablo Sánchez-martín, Shun Kageyama, Yu-shin Sou, Masato Koike, Satoshi Waguri, Masaaki KomatsuAbstract:p62/SQSTM1 is a multivalent protein that has the ability to cause liquid-liquid phase separation and serves as a receptor protein that participates in cargo isolation during selective autophagy. This protein is also involved in the non-canonical activation of the Keap1-Nrf2 system, a major oxidative stress response pathway. Here, we show a role of neighbor of BRCA1 gene 1 (NBR1), an autophagy receptor structurally similar to p62/SQSTM1, in p62-liquid droplet formation and Keap1-Nrf2 pathway activation. Overexpression of NBR1 blocks selective degradation of p62/SQSTM1 through autophagy and promotes the accumulation and phosphorylation of p62/SQSTM1 in liquid-like bodies, which is required for the activation of Nrf2. NBR1 is induced in response to oxidative stress, which triggers p62-mediated Nrf2 activation. Conversely, loss of NBR1 suppresses not only the formation of p62/SQSTM1-liquid droplets, but also of p62-dependent Nrf2 activation during oxidative stress. Taken together, our results show that NBR1 mediates p62/SQSTM1-liquid droplet formation to activate the Keap1-Nrf2 pathway.
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NBR1-mediated p62-liquid droplets enhance the Keap1-Nrf2 system
2019Co-Authors: Masaaki Komatsu, Pablo Sánchez-martín, Shun Kageyama, Yu-shin SouAbstract:p62/SQSTM1 is a multivalent protein that has an ability to cause a liquid-liquid phase separation and serves as a receptor protein that participates in cargo isolation during selective autophagy. This protein is also involved in the non-canonical activation of the Keap1-Nrf2 system, a major oxidative stress response pathway. Here we show a role of Neighbor of BRCA1 gene 1 (NBR1), an autophagy receptor structurally similar to p62/SQSTM1, in the p62-liquid droplet formation and the Keap1-Nrf2 pathway. The overexpression of NBR1 blocked selective degradation of p62/SQSTM1 through autophagy and promoted the accumulation and phosphorylation of p62/SQSTM1 in liquid-like bodies, which is required for the activation of Nrf2. NBR1 was induced in response to oxidative stress, and then the p62-mediated Nrf2 activation was up-regulated. Conversely, loss of NBR1 suppresses not only the formation of p62/SQSTM1-liquid droplets but also p62-dependent Nrf2 activation during oxidative stress. Taken together, our results show that NBR1 mediates p62/SQSTM1-liquid droplet formation to activate the Keap1-Nrf2 pathway.
