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Review
. 2023 Mar 20:10:1155521.
doi: 10.3389/fmolb.2023.1155521. eCollection 2023.

Reversible protein assemblies in the proteostasis network in health and disease

Verena Kohler  1 , Claes Andréasson  2
Affiliations
Review

Reversible protein assemblies in the proteostasis network in health and disease

Verena Kohler et al. Front Mol Biosci. .

Abstract

While proteins populating their native conformations constitute the functional entities of cells, protein aggregates are traditionally associated with cellular dysfunction, stress and disease. During recent years, it has become clear that large aggregate-like protein condensates formed via liquid-liquid phase separation age into more solid aggregate-like particles that harbor misfolded proteins and are decorated by protein quality control factors. The constituent proteins of the condensates/aggregates are disentangled by protein disaggregation systems mainly based on Hsp70 and AAA ATPase Hsp100 chaperones prior to their handover to refolding and degradation systems. Here, we discuss the functional roles that condensate formation/aggregation and disaggregation play in protein quality control to maintain proteostasis and why it matters for understanding health and disease.

Keywords: Hsp100; Hsp70; aggregate; biomolecular condensate; degradation; disaggregation; phase separation; refolding.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Influence of proteostatic stress on cellular fitness. (A) Upon increase of proteotoxic stress, cells activate stress response regimes, ensuring on keeping cellular processes functional. Overburden results in the collapse of the proteostasis system and occurrence of aggregates, leading to drastically decreased cellular healthspan. (B) Strategies of the cellular protein quality control system to counteract proteotoxic stress, end in the triage decision between refolding and degradation. Please see main text for details.
FIGURE 2
FIGURE 2
Simplified overview on phase separation and aggregation. (A) Upon presence of scaffold proteins with potent liquid-liquid phase separation (LLPS)-enabling features, de-mixing of a protein solution can take place, eventuation in liquid-like condensates, consisting of both scaffold (dark blue) and client (light blue) proteins. Ageing processes result in solid-like condensates that no longer support dynamic exchange of constituents with the surrounding milieu. Please note that also chaperones and protein quality control factors are involved in these processes. (B) Unfolded resp. partially unfolded protein species can adopt different aggregate forms. Depending on the intrinsic nature, amorphous as well as amyloid aggregates can occur, with a limited potential for recovery. Small heats hock proteins (sHsps) are responsible for targeted and regulated sequestration and alleviate subsequent recovery/refolding.
FIGURE 3
FIGURE 3
Simplified comparison between different disaggregation machineries. While bacteria, fungi and plants rely of disaggregation based on the activity of a Hsp100 isoform, supported by Hsp70, Hsp110 and a diverse set of J-domain proteins (JDP), metazoan disaggregation is based on Hsp70 activity, supported by co-chaperones belonging to the Hsp110 and JDP class. Please note that additional chaperones and protein quality control factors are involved to guarantee efficient disaggregation.
FIGURE 4
FIGURE 4
Overview of major cellular degradation pathways. (A) Before degradation via the ubiquitin-proteasome system (UPS), aggregated proteins require disaggregation, followed by decoration with poly-ubiquitin (Ub) moieties. This reaction is facilitated by ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2) and ubiquitin ligases (E3). Prior to degradation, ubiquitin moieties are removed by deubiquitinating enzymes (DUB). (B) Persistent aggregates are subjected towards autophagosomal degradation. To that end, p62 recognizing ubiquitin moieties facilitates the interaction of aggregates with LC3 on the growing autophagosome membrane. Please note that more proteins are involved to ensure efficient autophagy. After membrane closure, the autophagosome fuses with lysosomes in metazoan, leading to degradation of proteinaceous content (in autolysosomes). p62 (among other factors) serves to balance degradation via UPS and autophagy.
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