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Insights into the Role of P-Bodies and Stress Granules in Protein Quality Control.

ABSTRACT: The eukaryotic cell is highly compartmentalized, and contains a variety of both membrane-bound and membraneless organelles. The latter include the cytoplasmic ribonucleoprotein (RNP) granules, known as the processing body (P-body) and the stress granule. These RNP structures are thought to be involved in the storage of particular mRNAs during periods of stress. Here, we find that a mutant lacking both P-bodies and stress granules exhibits phenotypes suggesting that these structures also have a role in the maintenance of protein homeostasis. In particular, there was an increased occurrence of specific protein quality control (PQC) compartments in this mutant, an observation that is consistent with there being an elevated level of protein misfolding. These compartments normally house soluble misfolded proteins and allow the cell to sequester these polypeptides away from the remaining cellular milieu. Moreover, specific proteins that are normally targeted to both P-bodies and stress granules were found to instead associate with these PQC compartments in this granuleless mutant. This observation is interesting as our data indicate that this association occurs specifically in cells that have been subjected to an elevated level of proteotoxic stress. Altogether, the results here are consistent with P-bodies and stress granules having a role in normal protein homeostasis in eukaryotic cells.

SUBMITTER: Nostramo R

PROVIDER: S-EPMC6727810 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Insights into the Role of P-Bodies and Stress Granules in Protein Quality Control.

Nostramo Regina R Xing Siyuan S Zhang Bo B Herman Paul K PK

Genetics 20190708 1

The eukaryotic cell is highly compartmentalized, and contains a variety of both membrane-bound and membraneless organelles. The latter include the cytoplasmic ribonucleoprotein (RNP) granules, known as the processing body (P-body) and the stress granule. These RNP structures are thought to be involved in the storage of particular mRNAs during periods of stress. Here, we find that a mutant lacking both P-bodies and stress granules exhibits phenotypes suggesting that these structures also have a r ...[more]

PMID: 31285256

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Project description:Ribonucleoprotein (RNP) granules transport, store, or degrade messenger RNAs, thereby indirectly regulating protein synthesis. Normally, RNP granules are highly dynamic compartments. However, because of aging or severe environmental stress, RNP granules, in particular stress granules (SGs), convert into solid, aggregate-like inclusions. There is increasing evidence that such RNA-protein inclusions are associated with several age-related neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), fronto-temporal dementia (FTD) and Alzheimer's disease (AD). Thus, understanding what triggers the conversion of RNP granules into aggregates and identifying the cellular players that control RNP granules will be critical to develop treatments for these diseases. In this review article, we discuss recent insight into RNP and SG formation. More specifically, we examine the evidence for liquid-liquid phase separation (LLPS) as an organizing principle of RNP granules and the role of aggregation-prone RNA-binding proteins (RBPs) in this process. We further discuss recent findings that liquid-like SGs can sequester misfolded proteins, which promote an aberrant conversion of liquid SGs into solid aggregates. Importantly, very recent studies show that a specific protein quality control (PQC) process prevents the accumulation of misfolding-prone proteins in SGs and, by doing so, maintains the dynamic state of SGs. This quality control process has been referred to as granulostasis and it relies on the specific action of the HSPB8-BAG3-HSP70 complex. Additional players such as p97/valosin containing protein (VCP) and other molecular chaperones (e.g., HSPB1) participate, directly or indirectly, in granulostasis, and ensure the timely elimination of defective ribosomal products and other misfolded proteins from SGs. Finally, we discuss recent findings that, in the stress recovery phase, SGs are preferentially disassembled with the assistance of chaperones, and we discuss evidence for a back-up system that targets aberrant SGs to the aggresome for autophagy-mediated clearance. Altogether the findings discussed here provide evidence for an intricate network of interactions between RNP granules and various components of the PQC machinery. Molecular chaperones in particular are emerging as key players that control the composition and dynamics of RNP granules, which may be important to protect against age-related diseases.

Project description:Transcriptome analyses indicate that a core 10%-15% of the yeast genome is modulated by a variety of different stresses. However, not all the induced genes undergo translation, and null mutants of many induced genes do not show elevated sensitivity to the particular stress. Elucidation of the RNA lifecycle reveals accumulation of non-translating mRNAs in cytoplasmic granules, P-bodies, and stress granules for future regulation. P-bodies contain enzymes for mRNA degradation; under stress conditions mRNAs may be transferred to stress granules for storage and return to translation. Protein degradation by the ubiquitin-proteasome system is elevated by stress; and here we analyzed the steady state levels, decay, and subcellular localization of the mRNA of the gene encoding the F-box protein, UFO1, that is induced by stress. Using the MS2L mRNA reporter system UFO1 mRNA was observed in granules that colocalized with P-bodies and stress granules. These P-bodies stored diverse mRNAs. Granules of two mRNAs transported prior to translation, ASH1-MS2L and OXA1-MS2L, docked with P-bodies. HSP12 mRNA that gave rise to highly elevated protein levels was not observed in granules under these stress conditions. ecd3, pat1 double mutants that are defective in P-body formation were sensitive to mRNAs expressed ectopically from strong promoters. These highly expressed mRNAs showed elevated translation compared with wild-type cells, and the viability of the mutants was strongly reduced. ecd3, pat1 mutants also exhibited increased sensitivity to different stresses. Our interpretation is that sequestration of highly expressed mRNAs in P-bodies is essential for viability. Storage of mRNAs for future regulation may contribute to the discrepancy between the steady state levels of many stress-induced mRNAs and their proteins. Sorting of mRNAs for future translation or decay by individual cells could generate potentially different phenotypes in a genetically identical population and enhance its ability to withstand stress.

Dataset Information

Insights into the Role of P-Bodies and Stress Granules in Protein Quality Control.

Publications

Insights into the Role of P-Bodies and Stress Granules in Protein Quality Control.

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