Comparison of Intra-organellar Chaperone Capacity for Dealing with Stress-induced Protein Unfolding

Hageman, Jurre; Vos, Michel J.; Waarde, Maria A.W.H. van; Kampinga, Harm H.

doi:10.1074/jbc.m703876200

Cited by 39 publications

(44 citation statements)

References 57 publications

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“…It has been suggested that intranuclear inclusion formation of polyQ-expanded ATXN3 is promoted by the nuclear environment (11), and in fact, heat-induced denaturation of proteins is more rapid in the nuclear compartment compared with the cytoplasm, as demonstrated by biophysical (28) and biochemical (29,30) experiments. On the other hand, evidence has been provided that nuclear inclusions are active proteolytic centers (31).…”

Section: Discussionmentioning

confidence: 99%

Nuclear Aggregation of Polyglutamine-expanded Ataxin-3

Breuer

Haacke

Evert

et al. 2010

Journal of Biological Chemistry

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Expansion of a polymorphic polyglutamine segment is the common denominator of neurodegenerative polyglutamine diseases. The expanded proteins typically accumulate in large intranuclear inclusions and induce neurodegeneration. However, the mechanisms that determine the subcellular site and rate of inclusion formation are largely unknown. We found that the conserved putative nuclear localization sequence Arg-LysArg-Arg, which is retained in a highly aggregation-prone fragment of ataxin-3, did not affect the site and degree of inclusion formation in a cell culture model of spinocerebellar ataxia type 3. Addition of synthetic nuclear export or import signals led to the expected localization of ataxin-3 and determined the subcellular site of aggregate formation. Triggering a cellular stress response by heat shock transcription factor ⌬HSF1 coexpression abrogated aggregation in the cytoplasm but not in the nucleus. These findings indicate that native aggregation-prone fragments derived from expanded ataxin-3 may eventually escape the cytoplasmic quality control, resulting in aggregation in the nuclear compartment.Many human diseases are caused by the continuous expression of misfolded or misfolding-sensitive proteins (for review, see Ref. 1). The related polyglutamine (polyQ) 3 family of neurodegenerative diseases is caused by expansion of a variable polyQ segment above a threshold of typically ϳ40 residues. These expansions render the otherwise unrelated proteins susceptible to adopt non-native conformations that eventually become toxic or form toxic oligomers and aggregates. Large aggregates arise as intracellular inclusion bodies that are composed mainly of the mutant protein but also contain many other proteins, including transcription factors (2), molecular chaperones, and components of the ubiquitin-proteasome system (3). Several cellular pathways, including transcriptional dysregulation, inhibition of protein degradation, impairment of energy metabolism, and activation of cell death programs, have been implicated in the molecular mechanisms of the neurodegenerative processes caused by polyQ-expanded proteins (for review, see Ref. 4). These variations are likely determined by sequences outside the polyQ tract, which are specific for the individual disease proteins (5, 6). Even though toxicity has been experimentally dissociated from detectable inclusion body formation (e.g. Refs. 7 and 8), the hallmark of polyQ diseases is the characteristic formation of intraneuronal inclusions, most often in the nuclear compartment. Hence, it seems reasonable to argue that an imbalance in the production of toxic aggregation intermediates and their clearance constitutes the fundamental commonality of these diseases (9). Notably, the aggregation products accumulate, although cells are equipped with an elaborate network of molecular chaperones and cofactors with sufficient capacity to maintain a balanced protein homeostasis essential to cellular function (9, 10). Increasing evidence suggests that the nuclear compartment is the pr...

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Section: Discussionmentioning

confidence: 99%

Nuclear Aggregation of Polyglutamine-expanded Ataxin-3

Breuer

Haacke

Evert

et al. 2010

Journal of Biological Chemistry

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“…HSPA1A is a member of the Hsp70 family (30). In cooperation with other chaperones, HSPA1A mediates the folding of newly translated polypeptides in the cytosol, as well as within organelles (31).…”

Section: Discussionmentioning

confidence: 99%

Identification of proteins with different abundance associated with cell migration and proliferation in leiomyoma interstitial fluid by proteomics

et al. 2017

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Abstract. Uterine leiomyoma is the most common female reproductive tract benign tumor. Little is known about protein composition and changes in the leiomyoma interstitial fluid (IF). The present study focused on changes in protein abundance in the IF of leiomyoma. Leiomyoma IFs and adjacent myometrial IFs were obtained and analyzed by two-dimensional electrophoresis (2-DE) coupled with mass spectrometry and western blotting for 2-DE data validation. A total of 25 unique proteins were observed to change significantly (P<0.05). Of these proteins with different abundance, 22 had not been previously identified in leiomyoma IF. In silico analysis predicted that three of these proteins were secreted via classical mechanisms, while 22 were secreted via non-classical mechanisms. Ingenuity Pathway Analysis identified 17 proteins associated with cellular migration and proliferation. Among these, phosphoglycerate mutase 1 had not been previously associated with leiomyoma. The abundance of seven proteins was further validated by western blotting. A comparative proteomic approach identified a number of proteins associated with cellular migration and proliferation, with changes in abundance in IF likely to be involved in tumor development. Further studies will be required to investigate the role of these proteins in leiomyoma IF and their possible association with tumor development and growth.

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“…This could be due to two reasons; either the nuclear environment is highly dense and crowded with macromolecules which enhances the sensitivity of the Fluc variants to stress and/or, this can be due to the differences in the proteostasis capacity to deal with unfolded proteins. Indeed, it has been shown in past by many studies that the nuclear proteome is highly sensitive to stress and that nuclear damage following protein misfolding stress plays a very critical role in stress induced cell death (Hageman et al, 2007;Michels et al, 1997;Michels et al, 1995).…”

Section: Vi6 Analysis Of Intra-compartmental Proteostasis Capacity mentioning

confidence: 99%