Dynamic droplets: the role of cytoplasmic inclusions in stress, function, and disease

Abstract

Neurodegenerative diseases and other proteinopathies constitute a class of several dozen illnesses etiologically linked to pathological protein misfolding and aggregation. Because of this strong association with disease pathology, cell death, and aging, accumulation of proteins in aggregates or aggregation-associated structures (inclusions) has come to be regarded by many as a deleterious process, to be avoided if possible. Recent work has led us to see inclusion structures and disordered aggregate-like protein mixtures (which we call dynamic droplets) in a new light: not necessarily as a result of a pathological breakdown of cellular order, but as an elaborate cellular architecture regulating function and stress response. In this review, we discuss what is currently known about the role of inclusion structures in cellular homeostasis, stress response, toxicity, and disease. We will focus on possible mechanisms of aggregate toxicity, in contrast to the homeostatic function of several inclusion structures.

Fig. 1

Spatial architecture of protein folding quality control in yeast. Misfolded proteins are partitioned to distinct protein folding quality control compartments. This process is regulated by the ubiquitination status of the misfolded proteins, their solubility and concentration, and the availability of chaperones. Under acute stress misfolded proteins are initially trapped in stress foci, which are rapidly reversible structures. Over a longer time-scale, proteins that can be ubiquitinated and degraded are sent to the JUNQ for proteasomal degradation. Proteins that are not candidates for proteasomal degradation or are not ubiquitinated are targeted to the IPOD for active aggregation in an amyloid structure. It is unclear whether stress foci can merge with the IPOD

Fig. 2

Replicative rejuvenation in yeast. Misfolded and damaged proteins, aggregates, and old or damaged organelles are asymmetrically partitioned during mitosis through various mechanisms including compartmentalization and active transport on actin filaments. Retention of JUNQ and IPOD in mother cell is mediated by their attachment to the membranes of the nucleus and the vacuole, respectively. This process generates a daughter cell free from damage at the level of the proteome and with new “more fit” organelles

Fig. 3

Replicative rejuvenation in mammalian cells. Inclusions are asymmetrically inherited in mammalian cells during division. Daughter cells lacking JUNQ and IPOD may have survival advantage compared to daughter cell that retains the inclusions. Question marks imply mechanisms for asymmetry that are not yet clear