Functional Modules of the Proteostasis Network

Jayaraj, Gopal Gunanathan; Hipp, Mark S.; Hartl, F. Ulrich

doi:10.1101/cshperspect.a033951

Cited by 179 publications

(169 citation statements)

References 174 publications

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“…We previously showed that the TIS granule network localizes to the surface of the rough ER, which is the primary site of protein synthesis in most cells (9). As large proteins are more difficult to fold and proteins with large IDRs have a tendency to aggregate (24,25), we propose that translation in TIS granules provides a favorable environment during translation and folding of 'difficult to express' proteins under physiological conditions. This is based on the recent finding that RNA has a very potent chaperone function in vitro.…”

Section: Discussionmentioning

confidence: 97%

Unstructured mRNAs form multivalent RNA-RNA interactions to generate TIS granule networks

Zhao

Xie

et al. 2020

Preprint

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The TIS granule network is a constitutively expressed membraneless organelle that concentrates mRNAs with AU-rich elements and interacts with the major site of protein synthesis, the rough endoplasmic reticulum. Most known biomolecular condensates are spherelike, but TIS granules have a mesh-like morphology. Through in vivo and in vitro reconstitution experiments we discovered that this shape is generated by extensive intermolecular RNA-RNA interactions. They are mostly accomplished by mRNAs with large unstructured regions in their 3′UTRs that we call intrinsically disordered regions (IDRs). As AU-rich RNA is a potent chaperone that suppresses protein aggregation and is overrepresented in mRNAs with IDRs, our data suggests that TIS granules concentrate mRNAs that assist protein folding. In addition, the proximity of translating mRNAs in TIS granule networks may enable co-translational protein complex formation.Ma et al., page 2 Biomolecular condensates form through weak interactions of multivalent molecules. Proteinprotein interactions occur between repeated modular domains or between intrinsically disordered regions (IDRs). Protein IDRs lack a defined three-dimensional structure but often contain low-complexity sequence elements that provide the basis for multivalent intermolecular interactions (1). In addition, protein-RNA and RNA-RNA interactions contribute to the multivalency of phase separation systems (2-7). For example, it has been demonstrated that RNA can phase separate without protein and that RNA can promote or inhibit phase separation (3,8). It has also been shown that protein-RNA interactions can influence the identity and material properties of condensates in vitro and in vivo (2,4,6). However, the contribution of specific mRNAs to phase separation is largely unknown, as it has only been studied for few mRNAs (2,4).The TIS granule network is a membraneless organelle that forms a mesh-like compartment that is intertwined with the endoplasmic reticulum (ER). It is present in all cell types studied under physiological conditions. For mRNA to localize to TIS granules, they require several AU-rich elements in their 3′ untranslated regions (3′UTRs) (9). Whereas most known biomolecular condensates are sphere-like (1), TIS granules form a tubule-like meshwork. Here, we set out to investigate how the characteristic three-dimensional organization of TIS granules is determined.During these studies, we examined the influence of 47 human in vitro transcribed 3′UTRs, with sizes ranging from 500-5000 nucleotides, on phase separation of an RNA-binding protein. We observed that mRNAs that form strong local intramolecular interactions generate sphere-like condensates. In contrast, extensive intermolecular RNA-RNA interactions drive the generation of mesh-like condensates and are accomplished by mRNAs with large unstructured regions that are often single-stranded and AU-rich. Taken together, the TIS granule network represents a cytoplasmic compartment that concentrates unstructured, AU-rich mRNAs with a high propensit...

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Section: Discussionmentioning

confidence: 97%

Unstructured mRNAs form multivalent RNA-RNA interactions to generate TIS granule networks

Zhao

Xie

et al. 2020

Preprint

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“…The specific changes we observed herein focused our attention on the co-chaperone components (CARE) managing Hsp70 control of client folding as a central player in aging. In particular, the Bag3 response, being one of the largest differential responses detected, is involved in autophagic pathways, suggests that core chaperone associated degradation pathways associated with autophagy may be central to the management of AM and AT2 cells during aging, as suggested previously for other aging-related aggregation prone states (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). These observations raise the possibility that aging of the lung, a major contributor to the decline of lung function in response to environmental stress over a lifetime (9), is, at least in part, an uncharacterized aggregation prone disease, perhaps in response to supersaturation (83,84) that must be precisely managed by the extensive Bag and DnaJ families through CARE over a lifespan.…”

Section: Discussionmentioning

confidence: 69%

“…Additionally, we observed changes in the expression of multiple proteostasis components involved in the functionality of the Hsp70 and Hsp90 core chaperome complexes, which have previously been linked to the management of neurodegenerative and other protein misfolding challenges during aging (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). The specific changes we observed herein focused our attention on the co-chaperone components (CARE) managing Hsp70 control of client folding as a central player in aging.…”

Section: Discussionmentioning

confidence: 82%

“…We have presented the results of a comprehensive proteomic analysis of sorted AM and Although GO annotation reveals multiple adjustments to the proteome over the lifespan, two themes of contemporary relevance focused our attention on a subset of changes, namely mitochondrial related pathways (6,34-37,39,43,64,65) and proteostasis pathways (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28).…”

Section: Discussionmentioning

confidence: 99%

“…The long-term health of pulmonary tissue (2,6,8,(10)(11)(12)(13) is inextricably linked to the sustainability of the protein fold and its function (14)(15)(16)(17)(18). Protein homeostasis or proteostasis (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28), is a collection of integrated biological pathways, referred to as the proteostasis network (PN), that balance protein biosynthesis, folding, trafficking, post-translational modifications and clearance through multiple degradation pathways in response to endogenous and exogenous folding stress during aging (6,16,(18)(19)(20)(21)23,(25)(26)(27)29,30). Specifically, proteostasis components involved in protein folding management are referred to as the chaperome (31).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Proteostasis and Energetics as Proteome Hallmarks of Aging and Influenza Challenge in Pulmonary Disease

Loguercio

Hutt

Campos

et al. 2019

Preprint

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Aging is associated with an increased risk for the development of many diseases. This is exemplified by the increased incidence of lung injury, muscle dysfunction and cognitive impairment in the elderly following influenza infection. Because the infectious cycle of flu is dependent upon the properties of the host, we examined the proteome of alveolar macrophages (AM) and type 2 cells (AT2) obtained from young (3 months) and old (18 months) naïve mice and mice exposed to influenza A. Our proteomics data show that there is a maladaptive collapse of the proteostasis network (PN) and changes in mitochondrial pathways in the aged naïve AM and AT2 proteomes. The mitochondrial imbalance and proteostatic collapse seen in aged cells places an excessive folding burden on these cells, which is further exacerbated following exposure to influenza A. Specifically, we see an imbalance in Hsp70 co-chaperones involved in protein folding and Hsp90 co-chaperones important for stress signaling pathways that are essential for cellular protection during aging. The acute challenge of influenza A infection of young and aged AM and AT2 cells reveals that age-associated changes in the chaperome affect the ability of these cells to properly manage the infection and post-infection biology, contributing to cytotoxicity. We posit that proteomic profiling of individual cell type specific responses provides a high impact approach to pinpoint fundamental molecular relationships that may contribute to the susceptibility to aging and environmental stress, providing a platform to identify new targets for therapeutic intervention to improve resiliency in the elderly.

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The Mediator subunit MED12 promotes formation of HSF1 condensates on heat shock response element arrays in heat‐shocked cells

et al. 2023

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Upon heat shock, activated heat shock transcription factor 1 (HSF1) binds to the heat shock response elements (HSEs) in the promoters of mammalian heat shock protein (HSP)-encoding genes and recruits the preinitiation complex and coactivators, including Mediator. These transcriptional regulators may be concentrated in phase-separated condensates around the promoters, but they are too minute to be characterized in detail. We herein established HSF1 À/À mouse embryonic fibroblasts harbouring HSP72-derived multiple HSE arrays and visualized the condensates of fluorescent protein-tagged HSF1 with liquid-like properties upon heat shock. Using this experimental system, we demonstrate that endogenous MED12, a subunit of Mediator, is concentrated in artificial HSF1 condensates upon heat shock. Furthermore, the knockdown of MED12 markedly reduces the size of condensates, suggesting an important role for MED12 in HSF1 condensate formation.

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Functional Modules of the Proteostasis Network

Cited by 179 publications

References 174 publications

Unstructured mRNAs form multivalent RNA-RNA interactions to generate TIS granule networks

Unstructured mRNAs form multivalent RNA-RNA interactions to generate TIS granule networks

Proteostasis and Energetics as Proteome Hallmarks of Aging and Influenza Challenge in Pulmonary Disease

The Mediator subunit MED12 promotes formation of HSF1 condensates on heat shock response element arrays in heat‐shocked cells

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