Molecular Horizons Seminar - Thomas Walker

Heat shock proteins (Hsps) perform an essential role in the cellular proteostasis network to prevent the misfolding and aggregation of proteins. However, far less is known about their roles in maintaining proteostasis within biomolecular condensates formed through liquid-liquid phase separation (LLPS). Dysfunctional LLPS has emerged as a novel mechanism leading to the formation of pathological protein aggregates in amyotrophic lateral sclerosis (ALS). Recently, it was reported that the small heat shock protein HspB1 is a key regulator of TDP-43 phase separation and aggregation in the cytoplasm. This seminar outlines our investigation into the role of HspB1 and HspB5 in regulating the biophysical state of TDP-43 in a purified protein system and in cultured cells. Through this, we demonstrate that despite their high degree of structure homology, HspB1 and HspB5 engage in distinct interactions with TDP-43 that function to regulate the liquid-like state of TDP-43 biomolecular condensates and prevent the assembly of TDP-43 aggregates.