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2017 ; 10
(ä): 84
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Granulostasis: Protein Quality Control of RNP Granules
#MMPMID28396624
Alberti S
; Mateju D
; Mediani L
; Carra S
Front Mol Neurosci
2017[]; 10
(ä): 84
PMID28396624
show ga
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.
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