Cells recognize osmotic stress through liquid–liquid phase separation lubricated with poly(ADP-ribose)

Watanabe, K.; Morishita, Kazuhiro; Zhou, Xiangyu; Shiizaki, Shigeru; Uchiyama, Yasuo; Koike, Masato; Naguro, Isao; Ichijo, Hidenori

doi:10.1038/s41467-021-21614-5

Cited by 79 publications

(78 citation statements)

References 73 publications

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“…As was the case for BAG2 condensates (Fig. 3b ), previous studies have shown that phase separation in some proteins depends upon a coiled-coil domain as observed for ASK3 under hyperosmotic stress 47 or ORF1 RNA chaperone 48 . Interestingly, the BAG2 phosphorylation site at the first amino acid of the coiled-coil domain, modulates BAG2 phase separation (Fig.…”

Section: Discussionsupporting

confidence: 67%

Stress routes clients to the proteasome via a BAG2 ubiquitin-independent degradation condensate

et al. 2022

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The formation of membraneless organelles can be a proteotoxic stress control mechanism that locally condenses a set of components capable of mediating protein degradation decisions. The breadth of mechanisms by which cells respond to stressors and form specific functional types of membraneless organelles, is incompletely understood. We found that Bcl2-associated athanogene 2 (BAG2) marks a distinct phase-separated membraneless organelle, triggered by several forms of stress, particularly hyper-osmotic stress. Distinct from well-known condensates such as stress granules and processing bodies, BAG2-containing granules lack RNA, lack ubiquitin and promote client degradation in a ubiquitin-independent manner via the 20S proteasome. These organelles protect the viability of cells from stress and can traffic to the client protein, in the case of Tau protein, on the microtubule. Components of these ubiquitin-independent degradation organelles include the chaperone HSP-70 and the 20S proteasome activated by members of the PA28 (PMSE) family. BAG2 condensates did not co-localize with LAMP-1 or p62/SQSTM1. When the proteasome is inhibited, BAG2 condensates and the autophagy markers traffic to an aggresome-like structure.

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Section: Discussionsupporting

confidence: 67%

Stress routes clients to the proteasome via a BAG2 ubiquitin-independent degradation condensate

et al. 2022

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“…ASK3 bidirectionally responds to changes in osmolality, being phosphorylated and therefore activated under hypoosmotic conditions and in turn dephosphorylated and inactivated under hyperosmotic conditions, consequently regulating cell volume recovery. During hyperosmosis, liquid phase separation of ASK3 is necessary for its inactivation and PAR has been shown to maintain liquidity of those condensates, therefore presenting a supporting factor in osmotic stress regulation ( 140 ). For more detailed information on the involvement of PAR in biomolecular condensate formation, we would like to refer to a recent review article by Leung ( 100 ).…”

Section: Consequences Of Par Heterogeneity: Why Structure and Chain Length Mattermentioning

confidence: 99%

Why structure and chain length matter: on the biological significance underlying the structural heterogeneity of poly(ADP-ribose)

Reber

Mangerich

2021

Nucleic Acids Research

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Poly(ADP-ribosyl)ation (PARylation) is a multifaceted post-translational modification, carried out by poly(ADP-ribosyl)transferases (poly-ARTs, PARPs), which play essential roles in (patho-) physiology, as well as cancer therapy. Using NAD+ as a substrate, acceptors, such as proteins and nucleic acids, can be modified with either single ADP-ribose units or polymers, varying considerably in length and branching. Recently, the importance of PAR structural heterogeneity with regards to chain length and branching came into focus. Here, we provide a concise overview on the current knowledge of the biochemical and physiological significance of such differently structured PAR. There is increasing evidence revealing that PAR’s structural diversity influences the binding characteristics of its readers, PAR catabolism, and the dynamics of biomolecular condensates. Thereby, it shapes various cellular processes, such as DNA damage response and cell cycle regulation. Contrary to the knowledge on the consequences of PAR’s structural diversity, insight into its determinants is just emerging, pointing to specific roles of different PARP members and accessory factors. In the future, it will be interesting to study the interplay with other post-translational modifications, the contribution of natural PARP variants, and the regulatory role of accessory molecules. This has the exciting potential for new therapeutic approaches, with the targeted modulation and tuning of PARPs’ enzymatic functions, rather than their complete inhibition, as a central premise.

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“…Several groups have shown that PAR, a nucleic acid-mimicking biopolymer, can stimulate liquid demixing of IDPs or proteins with low-complexity regions in vitro or in vivo. For instance, a recent publication on apoptosis signal-regulating kinase 3 (ASK3) indicated that PAR could keep ASK3 condensates in the liquid phase and enable cells to sense osmotic stress (Watanabe et al, 2021). LLPS of SG components including fused in sarcoma (FUS), TDP-43, and hnRNP A1 are also regulated by PAR (Altmeyer et al, 2015;Patel et al, 2015;Kam et al, 2018;McGurk et al, 2018a;Duan et al, 2019;Singatulina et al, 2019).…”

Section: Poly(adp-ribose) Affects Protein Phase Separation Behavior Of Sg Componentsmentioning

confidence: 99%

Functional Roles of Poly(ADP-Ribose) in Stress Granule Formation and Dynamics

Jin

Cao

Liu

et al. 2021

Front. Cell Dev. Biol.

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Stress granules (SGs) are highly dynamic cytoplasmic foci formed in response to stress. The formation of SGs is reported to be regulated by diverse post-translational protein modifications (PTMs). Among them, ADP-ribosylation is of emerging interest due to its recently identified roles in SG organization. In this review, we summarized the latest advances on the roles of poly(ADP-ribose) (PAR) in the regulation of SG formation and dynamics, including its function in modulating nucleocytoplasmic trafficking and SG recruitment of SG components, as well as its effects on protein phase separation behavior. Moreover, the functional role of PAR chain diversity on dynamic of SG composition is also introduced. Potential future developments on investigating global ADP-ribosylation networks, individual roles of different PARPs, and interactions between ADP-ribosylation and other PTMs in SGs are also discussed.

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Cells recognize osmotic stress through liquid–liquid phase separation lubricated with poly(ADP-ribose)

Cited by 79 publications

References 73 publications

Stress routes clients to the proteasome via a BAG2 ubiquitin-independent degradation condensate

Stress routes clients to the proteasome via a BAG2 ubiquitin-independent degradation condensate

Why structure and chain length matter: on the biological significance underlying the structural heterogeneity of poly(ADP-ribose)

Functional Roles of Poly(ADP-Ribose) in Stress Granule Formation and Dynamics

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