Ref(2)P, the <i>Drosophila melanogaster</i> homologue of mammalian p62, is required for the formation of protein aggregates in adult brain

Nezis, Ioannis P.; Simonsen, Anne; Sagona, Antonia P.; Finley, Kim D.; Gaumer, Sébastien; Contamine, Didier; Rusten, Tor Erik; Stenmark, Harald; Brech, Andreas

doi:10.1083/jcb.200711108

Cited by 341 publications

(371 citation statements)

References 23 publications

(31 reference statements)

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“…Abundant protein aggregates increased levels of the mammalian autophagy cargo receptor p62 and the Drosophila orthologue Ref(2)P (Nezis et al., 2008). The p62 [Ref(2)P] protein binds Keap1, sequestering it from Nrf2 (CncC) in the cytoplasm, thereby allowing Nrf2 (CncC) to translocate into the nucleus (Dialynas et al., 2015; Jain et al., 2010).…”

Section: Resultsmentioning

confidence: 99%

Increasing autophagy and blocking Nrf2 suppress laminopathy‐induced age‐dependent cardiac dysfunction and shortened lifespan

et al. 2018

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SummaryMutations in the human LMNA gene cause a collection of diseases known as laminopathies. These include myocardial diseases that exhibit age‐dependent penetrance of dysrhythmias and heart failure. The LMNA gene encodes A‐type lamins, intermediate filaments that support nuclear structure and organize the genome. Mechanisms by which mutant lamins cause age‐dependent heart defects are not well understood. To address this issue, we modeled human disease‐causing mutations in the Drosophila melanogaster Lamin C gene and expressed mutant Lamin C exclusively in the heart. This resulted in progressive cardiac dysfunction, loss of adipose tissue homeostasis, and a shortened adult lifespan. Within cardiac cells, mutant Lamin C aggregated in the cytoplasm, the CncC(Nrf2)/Keap1 redox sensing pathway was activated, mitochondria exhibited abnormal morphology, and the autophagy cargo receptor Ref2(P)/p62 was upregulated. Genetic analyses demonstrated that simultaneous over‐expression of the autophagy kinase Atg1 gene and an RNAi against CncC eliminated the cytoplasmic protein aggregates, restored cardiac function, and lengthened lifespan. These data suggest that simultaneously increasing rates of autophagy and blocking the Nrf2/Keap1 pathway are a potential therapeutic strategy for cardiac laminopathies.

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Section: Resultsmentioning

confidence: 99%

Increasing autophagy and blocking Nrf2 suppress laminopathy‐induced age‐dependent cardiac dysfunction and shortened lifespan

et al. 2018

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“…Interestingly, p62/SQSTM1 must oligomerize to localize the aggregates to autophagosome-forming structures and for efficient engulfment and delivery of autophagy substrates (Itakura and Mizushima 2011). These findings suggest that p62/ SQSTM1 is more than just an adaptor protein between autophagy and its substrates, but is an active component of the autophagic process (Komatsu et al 2007;Nezis et al 2008). Furthermore, p62/SQSTM1 can mediate autophagic clearance of non-ubiquitylated protein aggregates as well, by binding them through the PB1 domain (Watanabe and Tanaka 2011).…”

Section: Autophagy and Protein Degradationmentioning

confidence: 99%

p62/SQSTM1 at the interface of aging, autophagy, and disease

Bitto

Lerner

Nacarelli

et al. 2014

AGE

122

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Advanced age is characterized by increased incidence of many chronic, noninfectious diseases that impair the quality of living of the elderly and pose a major burden on the healthcare systems of developed countries. These diseases are characterized by impaired or altered function at the tissue and cellular level, which is a hallmark of the aging process. Age-related impairments are likely due to loss of homeostasis at the cellular level, which leads to the accumulation of dysfunctional organelles and damaged macromolecules, such as proteins, lipids, and nucleic acids. Intriguingly, aging and age-related diseases can be delayed by modulating nutrient signaling pathways converging on the target of rapamycin (TOR) kinase, either by genetic or dietary intervention. TOR signaling influences aging through several potential mechanisms, such as autophagy, a degradation pathway that clears the dysfunctional organelles and damaged macromolecules that accumulate with aging. Autophagy substrates are targeted for degradation by associating with p62/SQSTM1, a multidomain protein that interacts with the autophagy machinery. p62/SQSTM1 is involved in several cellular processes, and its loss has been linked to accelerated aging and to age-related pathologies. In this review, we describe p62/SQSTM1, its role in autophagy and in signaling pathways, and its emerging role in aging and age-associated pathologies. Finally, we propose p62/ SQSTM1 as a novel target for aging studies and ageextending interventions.

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“…Interestingly, vesicular stomatitis virus, which is a fairly close relative to the sigma viruses, activates autophagy in D. melanogaster, which protects the flies against the virus [82]. Ref(2)P is an adaptor protein which selectively targets polyubiquitinated substrates for degradation by autophagy [83], and its mammalian homologue, p62, has been found to target bacteria for degradation by autophagy [84]. It therefore seems likely the involvement of ref (2)…”

Section: Resistance To Sigma Virusesmentioning

confidence: 99%

Vertically transmitted viral endosymbionts of insects: do sigma viruses walk alone?

Longdon

Jiggins

2012

Proc. R. Soc. B.

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Insects are host to a wide range of vertically transmitted bacterial endosymbionts, but we know relatively little about their viral counterparts. Here, we discuss the vertically transmitted viral endosymbionts of insects, firstly examining the diversity of this group, and then focusing on the well-studied sigma viruses that infect dipterans. Despite limited sampling, evidence suggests that vertically transmitted viruses may be common in insects. Unlike bacteria, viruses can be transmitted through sperm and eggs, a trait that allows them to rapidly spread through host populations even when infection is costly to the host. Work on Drosophila melanogaster has shown that sigma viruses and their hosts are engaged in a coevolutionary arms race, in which the spread of resistance genes in the host population is followed by the spread of viral genotypes that can overcome host resistance. In the long-term, associations between sigma viruses and their hosts are unstable, and the viruses persist by occasionally switching to new host species. It therefore seems likely that viral endosymbionts have major impacts on the evolution and ecology of insects.

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Ref(2)P, the Drosophila melanogaster homologue of mammalian p62, is required for the formation of protein aggregates in adult brain

Cited by 341 publications

References 23 publications

Increasing autophagy and blocking Nrf2 suppress laminopathy‐induced age‐dependent cardiac dysfunction and shortened lifespan

Increasing autophagy and blocking Nrf2 suppress laminopathy‐induced age‐dependent cardiac dysfunction and shortened lifespan

p62/SQSTM1 at the interface of aging, autophagy, and disease

Vertically transmitted viral endosymbionts of insects: do sigma viruses walk alone?

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