scholarly journals The Chromatin Remodeler ISW1 Is a Quality Control Factor that Surveys Nuclear mRNP Biogenesis

Cell ◽  
2016 ◽  
Vol 167 (5) ◽  
pp. 1201-1214.e15 ◽  
Author(s):  
Anna Babour ◽  
Qingtang Shen ◽  
Julien Dos-Santos ◽  
Struan Murray ◽  
Alexandre Gay ◽  
...  
Keyword(s):  
Quality Control ◽  
Control Factor ◽  
Chromatin Remodeler ◽  
Mrnp Biogenesis

scholarly journals Quality control in oocytes by p63 is based on a spring-loaded activation mechanism on the molecular and cellular level

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Daniel Coutandin ◽  
Christian Osterburg ◽  
Ratnesh Kumar Srivastav ◽  
Manuela Sumyk ◽  
Sebastian Kehrloesser ◽  
...  
Keyword(s):  
Dna Damage ◽  
Quality Control ◽  
Cellular Level ◽  
Activation Mechanism ◽  
Control Factor ◽  
Dna Double Strand Breaks ◽  
High Concentration ◽  
P53 Family ◽  
Strand Breaks ◽  
Induced Apoptosis

Mammalian oocytes are arrested in the dictyate stage of meiotic prophase I for long periods of time, during which the high concentration of the p53 family member TAp63α sensitizes them to DNA damage-induced apoptosis. TAp63α is kept in an inactive and exclusively dimeric state but undergoes rapid phosphorylation-induced tetramerization and concomitant activation upon detection of DNA damage. Here we show that the TAp63α dimer is a kinetically trapped state. Activation follows a spring-loaded mechanism not requiring further translation of other cellular factors in oocytes and is associated with unfolding of the inhibitory structure that blocks the tetramerization interface. Using a combination of biophysical methods as well as cell and ovary culture experiments we explain how TAp63α is kept inactive in the absence of DNA damage but causes rapid oocyte elimination in response to a few DNA double strand breaks thereby acting as the key quality control factor in maternal reproduction.

scholarly journals Spatial quality control bypasses cell-based limitations on proteostasis to promote prion curing

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Courtney L Klaips ◽  
Megan L Hochstrasser ◽  
Christine R Langlois ◽  
Tricia R Serio
Keyword(s):  
Quality Control ◽  
Molecular Chaperone ◽  
Protein Misfolding ◽  
Elevated Temperatures ◽  
Control Factor ◽  
Control Mechanisms ◽  
Cellular Environment ◽  
Effective Activity ◽  
Spatial Quality

The proteostasis network has evolved to support protein folding under normal conditions and to expand this capacity in response to proteotoxic stresses. Nevertheless, many pathogenic states are associated with protein misfolding, revealing in vivo limitations on quality control mechanisms. One contributor to these limitations is the physical characteristics of misfolded proteins, as exemplified by amyloids, which are largely resistant to clearance. However, other limitations imposed by the cellular environment are poorly understood. To identify cell-based restrictions on proteostasis capacity, we determined the mechanism by which thermal stress cures the [PSI+]/Sup35 prion. Remarkably, Sup35 amyloid is disassembled at elevated temperatures by the molecular chaperone Hsp104. This process requires Hsp104 engagement with heat-induced non-prion aggregates in late cell-cycle stage cells, which promotes its asymmetric retention and thereby effective activity. Thus, cell division imposes a potent limitation on proteostasis capacity that can be bypassed by the spatial engagement of a quality control factor.

scholarly journals Phosphorylation of the C-terminal tail of proteasome subunit α7 is required for binding of the proteasome quality control factor Ecm29

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Prashant S. Wani ◽  
Anjana Suppahia ◽  
Xavier Capalla ◽  
Alex Ondracek ◽  
Jeroen Roelofs
Keyword(s):  
Quality Control ◽  
Control Factor ◽  
Proteasome Subunit

scholarly journals A novel UGGT1 and p97-dependent checkpoint for native ectodomains with ionizable intramembrane residue

2015 ◽  
Vol 26 (8) ◽  
pp. 1532-1542 ◽  
Author(s):  
Jessica Merulla ◽  
Tatiana Soldà ◽  
Maurizio Molinari
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Structural Defects ◽  
Control Factor ◽  
Loss Of Function ◽  
Functional Protein ◽  
Aaa Atpase ◽  
Golgi Transport ◽  
Defects Identification ◽  
Pharmacologic Inhibition

Only native polypeptides are released from the endoplasmic reticulum (ER) to be transported at the site of activity. Persistently misfolded proteins are retained and eventually selected for ER-associated degradation (ERAD). The paradox of a structure-based protein quality control is that functional polypeptides may be destroyed if they are architecturally unfit. This has health-threatening implications, as shown by the numerous “loss-of-function” proteopathies, but also offers chances to intervene pharmacologically to promote bypassing of the quality control inspection and export of the mutant, yet functional protein. Here we challenged the ER of human cells with four modular glycopolypeptides designed to alert luminal and membrane protein quality checkpoints. Our analysis reveals the unexpected collaboration of the cytosolic AAA-ATPase p97 and the luminal quality control factor UDP-glucose:glycoprotein glucosyltransferase (UGGT1) in a novel, BiP- and CNX-independent checkpoint. This prevents Golgi transport of a chimera with a native ectodomain that passes the luminal quality control scrutiny but displays an intramembrane defect. Given that human proteopathies may result from impaired transport of functional polypeptides with minor structural defects, identification of quality checkpoints and treatments to bypass them as shown here upon silencing or pharmacologic inhibition of UGGT1 or p97 may have important clinical implications.

scholarly journals Conservation of mRNA quality control factor Ski7 and its diversification through changes in alternative splicing and gene duplication

2018 ◽  
Vol 115 (29) ◽  
pp. E6808-E6816 ◽  
Author(s):  
Alexandra N. Marshall ◽  
Jaeil Han ◽  
Minseon Kim ◽  
Ambro van Hoof
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Quality Control ◽  
Alternative Splicing ◽  
Gene Duplication ◽  
Transcriptome Analysis ◽  
Control Factor ◽  
Intrinsically Disordered ◽  
Alternatively Spliced ◽  
Rna Exosome ◽  
Close Relatives

Eukaryotes maintain fidelity of gene expression by preferential degradation of aberrant mRNAs that arise by errors in RNA processing reactions. In Saccharomyces cerevisiae, Ski7 plays an important role in this mRNA quality control by mediating mRNA degradation by the RNA exosome. Ski7 was initially thought to be restricted to Saccharomyces cerevisiae and close relatives because the SKI7 gene and its paralog HBS1 arose by whole genome duplication (WGD) in a recent ancestor. We have recently shown that the preduplication gene was alternatively spliced and that Ski7 function predates WGD. Here, we use transcriptome analysis of diverse eukaryotes to show that diverse eukaryotes use alternative splicing of SKI7/HBS1 to encode two proteins. Although alternative splicing affects the same intrinsically disordered region of the protein, the pattern of splice site usage varies. This alternative splicing event arose in an early eukaryote that is a common ancestor of plants, animals, and fungi. Remarkably, through changes in alternative splicing and gene duplication, the Ski7 protein has diversified such that different species express one of four distinct Ski7-like proteins. We also show experimentally that the Saccharomyces cerevisiae SKI7 gene has undergone multiple changes that are incompatible with the Hbs1 function and may also have undergone additional changes to optimize mRNA quality control. The combination of transcriptome analysis in diverse eukaryotes and genetic analysis in yeast clarifies the mechanism by which a Ski7-like protein is expressed across eukaryotes and provides a unique view of changes in alternative splicing patterns of one gene over long evolutionary time.

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