The nascent polypeptide-associated complex is a key regulator of proteostasis

Kirstein, Janine; Scior, Annika; Deuerling, Elke; Morimoto, Richard I.

doi:10.1038/emboj.2013.87

Cited by 140 publications

(165 citation statements)

References 51 publications

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“…The CNV approach highlighted an age‐dependent decrease in members of the cytosolic ribosome and an increase in the proteasome, relative to their respective cell compartment (Mann–Whitney test P < 0.01; Fig EV5 and Dataset EV6). Indeed, the same age‐related variations were observed by the authors of the original publication, and they are corroborated by other independent studies (Hsu et al , 2003; Golden & Melov, 2004; Vilchez et al , 2012; Kirstein‐miles et al , 2013). …”

Section: Resultssupporting

confidence: 85%

Quantifying compartment‐associated variations of protein abundance in proteomics data

Parca

Beck

Bork

et al. 2018

Molecular Systems Biology

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Quantitative mass spectrometry enables to monitor the abundance of thousands of proteins across biological conditions. Currently, most data analysis approaches rely on the assumption that the majority of the observed proteins remain unchanged across compared samples. Thus, gross morphological differences between cell states, deriving from, e.g., differences in size or number of organelles, are often not taken into account. Here, we analyzed multiple published datasets and frequently observed that proteins associated with a particular cellular compartment collectively increase or decrease in their abundance between conditions tested. We show that such effects, arising from underlying morphological differences, can skew the outcome of differential expression analysis. We propose a method to detect and normalize morphological effects underlying proteomics data. We demonstrate the applicability of our method to different datasets and biological questions including the analysis of sub‐cellular proteomes in the context of Caenorhabditis elegans aging. Our method provides a complementary perspective to classical differential expression analysis and enables to uncouple overall abundance changes from stoichiometric variations within defined group of proteins.

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Section: Resultssupporting

confidence: 85%

Quantifying compartment‐associated variations of protein abundance in proteomics data

Parca

Beck

Bork

et al. 2018

Molecular Systems Biology

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“…The naca gene encodes the a subunit of the heterodimeric nascent polypeptide-associated complex (aNAC/ NACA), which binds to nascent polypeptides on the ribosome 11 . NACA appears to be part of the chaperon system that ensures the proper folding of nascent proteins, notably those to be translocated in the endoplasmic reticulum, ER 12,13 . The naca gene also encodes a muscle-specific, much larger isoform, skNAC, through differential RNA splicing 14,15 .…”

Section: Resultsmentioning

confidence: 99%

NACA deficiency reveals the crucial role of somite-derived stromal cells in haematopoietic niche formation

et al. 2015

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“…Ageing affects the proteome of C. elegans by the upregulation of proteins involved in the UPS, oxidative stress defence, and DNA replication and repair, and downregulation of ER, mitochondrial, and ribosomal proteins 25 . The decline in ribosomal proteins corresponds with age related slowing of protein synthesis rate 58 . Interestingly, reduc tion of protein synthesis was found to extend lifespan of D. melano gaster 59 , probably because of diminishing demand on the PQC to assist in the folding, transport, and clearance of proteins.…”

Section: Derailment During Normal Ageingmentioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

138

126

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The worldwide increase in life expectancy gives rise to an increasing prevalence of cardiac diseases, which remain the leading cause of disability and death in the developed world [1][2][3] . Currently, the mechanisms under lying how ageing contributes to the initiation or acceler ation of cardiac diseases are essentially unresolved. Prevailing theories of ageing centre on gradual derail ment of cellular protein homeostasis -proteostasis -either by design (genetically) or by 'wear and tear' (environmentally) 3 . Central to the role of proteostasis derailment as a major factor in ageing is the observation that protein function declines over time.Proteins are the most versatile and complex macro molecules and are involved in the proper functioning of every biological process 4 . After synthesis as a poly peptide chain from the genetic code, proper function of a protein relies heavily on its correct folding into a 3D native state and on various post translational modifi cations, mostly involving the addition of chem ical groups (including phosphate, acetate, and carbo hydrate). Protein maturation, transport, and ultimately breakdown is monitored and supported by various classes of proteins, collectively called 'protein quality control' (PQC) [3][4][5] . Balanced proteostasis, therefore, depends on proper PQC and is crucial for cellular and organismal health 6 . The intricate network making up the PQC involves numerous proteins, of which the main players are the chaperones and their regula tors 4,7-9 (assisting in folding and refolding of proteins) and the pathways that clear irreversibly misfolded and aggregation prone proteins (the ubiquitin-proteasome system [UPS] and autophagy systems) 9-11 . With ageing, the gradual accumulation of misfolded or damaged pro teins, together with concomitant failure of PQC, results in proteotoxic stress and compromised defence against reactive oxygen species (ROS) 10 , a process that is likely to be accelerated in various age related diseases includ ing neurodegenerative diseases 12,13 , type 2 diabetes mel litus 14 , cancer 15 , and cardiac diseases [16][17][18][19][20] . In addition to the accumulation of misfolded proteins, ageing is accompanied by an imbalance in the proteome, as indi cated by lowered expression of chaperone, proteaso mal, ribosomal, and mitochondrial proteins, whereas proteins related to oxidative stress are upregulated 21,22 . Although mild impairment of proteostasis extends lifespan in Caenorhabditis elegans, referred to as hormesis, sustained impairment is accompanied by loss of PQC to neutralize this effect 3,5 . Importantly, evidence indicates that the amount of soluble, aggregate prone protein oligomers, rather than the abundance of pro tein aggregates, correlates with disease severity 23,24 . Therefore, protein aggregates, which contain both misfolded proteins and elevated levels of chaper ones, constitute an adequate PQC response, aimed at sequestering potentially harmful protein oligomers, rather than embodying the ultimate cellular threat 25 . This ...

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The nascent polypeptide-associated complex is a key regulator of proteostasis

Cited by 140 publications

References 51 publications

Quantifying compartment‐associated variations of protein abundance in proteomics data

Quantifying compartment‐associated variations of protein abundance in proteomics data

NACA deficiency reveals the crucial role of somite-derived stromal cells in haematopoietic niche formation

Proteostasis in cardiac health and disease

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