A widespread family of heat-resistant obscure (Hero) proteins protect against protein instability and aggregation

Abstract

Proteins are typically denatured and aggregated by heating at near-boiling temperature. Exceptions to this principle include highly disordered and heat-resistant proteins found in extremophiles, which help these organisms tolerate extreme conditions such as drying, freezing, and high salinity. In contrast, the functions of heat-soluble proteins in non-extremophilic organisms including humans remain largely unexplored. Here, we report that heatresistant obscure (Hero) proteins, which remain soluble after boiling at 95˚C, are widespread in Drosophila and humans. Hero proteins are hydrophilic and highly charged, and function to stabilize various "client" proteins, protecting them from denaturation even under stress conditions such as heat shock, desiccation, and exposure to organic solvents. Hero proteins can also block several different types of pathological protein aggregations in cells and in Drosophila strains that model neurodegenerative diseases. Moreover, Hero proteins can extend life span of Drosophila. Our study reveals that organisms naturally use Hero proteins as molecular shields to stabilize protein functions, highlighting their biotechnological and therapeutic potential.

BBLN-1 is essential for intermediate filament organization and apical membrane morphology

“…BBLN was found in a search for highly heat-resistant proteins that protect different subsets of proteins from aggregation or denaturation under stress conditions. 46 Indeed, BBLN is differentially expressed in diseases characterized by protein aggregation, including amyotrophic lateral sclerosis (ALS), 47 Alzheimer's, 48 and Parkinson's disease. 49 As the loss of BBLN-1 leads to IF aggregation, a potential future avenue of investigation is to examine whether BBLN-1 plays a direct role in protecting against protein aggregation.…”

BBLN-1 is essential for intermediate filament organization and apical membrane morphology

“…A final intriguing hypothesis is that BBLN-1 is involved in protein aggregation. Bublin was found in a search for highly heat-resistant proteins that remain soluble upon boiling (Tsuboyama et al, 2020). The identified proteins, termed ‘Hero’ for heat-resistant obscure proteins, were shown to protect different subsets of proteins from aggregation or denaturation under stress conditions (Tsuboyama et al, 2020).…”

“…Bublin was found in a search for highly heat-resistant proteins that remain soluble upon boiling (Tsuboyama et al, 2020). The identified proteins, termed ‘Hero’ for heat-resistant obscure proteins, were shown to protect different subsets of proteins from aggregation or denaturation under stress conditions (Tsuboyama et al, 2020). Indeed, bublin is differentially expressed in diseases characterized by protein aggregation, including amyotrophic lateral sclerosis (ALS) (Nijssen et al, 2018), Alzheimer’s (Kong et al, 2009), and Parkinson’s disease (Kim et al, 2020).…”

Phase Separation and Neurodegenerative Diseases: A Disturbance in the Force

“…These models offer the advantage of in vivo imaging at the subcellular resolution and with relatively low cost compared with larger animal models. Moreover, these models allow for exploring protein aggregation mechanisms in living organisms (David et al, 2010;Lobos-Ruiz et al, 2018;Tsuboyama et al, 2020) and are powerful for high-throughput screening of therapeutic compounds for neurodegenerative diseases (Chen et al, 2015;Franç ois-Moutal et al, 2019;Lobos-Ruiz et al, 2018).…”