Proteasome phase separation for destruction

April 27, 2020

The proteasome is a major proteolytic machine that regulates cellular proteostasis through selective degradation of ubiquitylated proteins. As the maintenance of protein homeostasis is essential to human health, malfunctions of the ubiquitin-proteasome system (UPS) causes various diseases such as cancers, inflammation, and neurodegeneration. However, we do not yet know the overall principles behind UPS.

In this study, the research team discovered a novel mode of protein degradation by the UPS under a stress condition.

"Around 2013, we discovered that proteasomes form nuclear foci in response to hyperosmotic stimuli. It was very impressive because the uniformly distributed proteasomes form foci in just a few seconds, but it took time to understand what this phenomenon means until we know liquid-liquid phase separation (LLPS). LLPS is a rapid, reversible, and wide-spread compartmentalization mechanism in cells. The proteasome foci actually exhibit liquid-like behavior and a series of experiments revealed the LLPS of proteasomes is for degradation of ubiquitylated proteins." said Yasushi Saeki, PhD, a lead author of the study.

The research results were published in Nature on February 5, 2020.

The hyperosmotic stress-induced proteasome droplets are a transient structure that disappears within a few hours after sucrose treatment. The proteasome droplets also contain ubiquitylated substrates and multiple proteasome-interacting proteins. The formation of the proteasome droplets is dependent on protein ubiquitylation and their disappearance is dependent on the activity of the proteasome, indicating that the droplets facilitate protein degradation. Acute hyperosmotic stress causes a decrease in cell volume and nucleolar stress, resulting in the failure of ribosome biosynthesis as well as accumulation of orphan ribosomal proteins as major UPS substrate in the nucleoplasm. Indeed, hyperosmotic stress induces ubiquitylation of ribosomal proteins and their degradation at the proteasome droplets. Thus, elevated levels of ubiquitylated proteins trigger the formation of the proteasome droplets.

Dr. Saeki and his colleagues further investigated how the proteasomes are recruited to this fluidic subcompartment. The research group identified RAD23B, a substrate shuttling factor of the proteasome, as a key molecule that induces LLPS of ubiquitylated clients as well as the proteasome. RAD23B has two typical ubiquitin-binding domains (UBA) and one proteasome-binding domain (UBL). The group successfully reconstituted RAD23B- and ubiquitin-containing droplets in vitro and showed that weak multivalent interactions between the RAD23B UBA domains and long polymeric ubiquitin chains drive co-phase separation. Taken together, RAD23B collects cellular ubiquitylated proteins via the UBA domains to form droplets, and then recruit the proteasomes via the UBL domain.

"This study is a good example of the interplay between ubiquitin signaling and LLPS. Given that ubiquitin mainly functions as a polymer, one of the biological meaning of the polymerization may be for LLPS. It will be greatly interesting to investigate whether other ubiquitin-binding proteins undergo phase separation." said Dr. Saeki. "Also, it has been suggested that aggregation-prone proteins convert from liquid-like droplets to solid-like assemblies. In this context, acute hyperosmotic stress may risk irreversible accumulation of protein aggregates, especially when the proteasome activity is reduced."
-end-


Tokyo Metropolitan Institute of Medical Science

Related Proteasome Articles from Brightsurf:

How cell processes round up and dump damaged proteins
Reporting unexpected processes, chemist Eric Strieter at UMass Amherst says he and his group have discovered how an enzyme known as UCH37 regulates a cell's waste management system.

Photopharmacology - A light-trigger for the proteasome
Ludwig-Maximilians-Universitaet (LMU) in Munich researchers have designed a light-sensitive inhibitor that can control cell division and cell death - and provides a promising approach for studies of essential cellular processes and the development of novel tumor therapies.

Why do structural differences in α-synuclein aggregates cause different pathologies?
Abnormal α-synuclein aggregation has been implicated in several neurodegenerative diseases and is known to spread in a prion-like manner.

New insight into the evolution of complex life on Earth
A novel connection between primordial organisms and complex life has been discovered, as new evidence sheds light on the evolutionary origins of the cell division process that is fundamental to complex life on Earth.

Chemists build natural anti-cancer compound with lean new process
Creative chemists employ enzymes to build a complex but promising natural anti-cancer agent called cepafungin I in a lean nine steps.

Erectile dysfunction drugs can help cells destroy misfolded proteins
PDE5 inhibitors -- which include the erectile dysfunction drugs sildenafil and tadalafil -- can activate the cell's protein quality-control systems and improve its ability to dispose of misfolded proteins.

How are misfolded membrane proteins cleared from cells by "reubiquitinase"?
Chinese researchers recently discovered a protein quality control mechanism called ''reubiquitination'', which could promote the elimination of misfolded membrane proteins, minimize their dwell time in cells, and thereby reduce their probability to form toxic aggregates in human body.

Proteasome phase separation for destruction
Researchers at the Tokyo Metropolitan Institute of Medical Science (TMiMS) discovered proteasome-containing droplets, which are formed by acute hyperosmotic stress.

Mutation reduces energy waste in plants
In a way, plants are energy wasters: in order to protect themselves from excessive electron transport, they continuously quench light energy and don't use it for photosynthesis and biomass production.

Ancient Greek tholos-like architecture composed of archaeal proteins
Collaborative research groups discovered a unique supramolecular structure composed of hyperthermophilic archaeal proteins.

Read More: Proteasome News and Proteasome Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.