Droplet organelles?

Abstract

Cells contain numerous, molecularly distinct cellular compartments that are not enclosed by lipid bilayers. These compartments are implicated in a wide range of cellular activities, and they have been variously described as bodies, granules, or organelles. Recent evidence suggests that a liquid-liquid phase separation (LLPS) process may drive their formation, possibly justifying the unifying term "droplet organelle". A veritable deluge of recent publications points to the importance of low-complexity proteins and RNA in determining the physical properties of phase-separated structures. Many of the proteins linked to such structures are implicated in human diseases, such as amyotrophic lateral sclerosis (ALS). We provide an overview of the organizational principles that characterize putative "droplet organelles" in healthy and diseased cells, connecting protein biochemistry with cell physiology.

Keywords: Liquid‐liquid phase separation; RNP granules; low‐complexity domain; nuclear bodies.

Figure 1. In homeostatic cellular conditions, dynamic fluid droplets demix from surrounding nucleoplasm

(A) Nucleoli, Cajal bodies (CBs), histone locus bodies (HLBs), speckles, and paraspeckles participate in RNA and RNP biogenesis in the nucleus. Associated with chromosomal loci, these nuclear bodies contain specific RNAs and proteins that pass in and out of nuclear bodies during RNP assembly. Unstable RNAs concentrate in P bodies in the cytoplasm, where mRNA decay factors co‐localize. (B) Analogous dynamics and fluid properties are obtained when a purified RNA‐binding protein with a low‐complexity region is incubated in with RNA and observed over time in vitro. (C) Electron micrograph of a droplet showing overall spherical shape with an irregular outline. Micrographs reproduced from Li et al (2012).

Figure 2. During cellular stress, hydrogel‐like assemblies form

(A) Stressors like heat shock, UV light, and transcription inhibition can cause cellular bodies to disassemble (CBs), change morphology (nucleoli, nuclear speckles), or appear de novo (stress bodies). (B) These granules contain proteins that form hydrogels and ultimately form an intricate proteinaceous network or aggregate (C). Micrographs reproduced from Hennig et al (2015).

Figure 3. In disease, amyloid fibers arise from droplets

(A) Amyloid fibers can form in the nucleus or cytoplasm when constituent low‐complexity proteins are mutant. Concomitant changes in nuclear morphology have not been reported. (B) In vitro, fiber formation by mutant proteins, such as FUS, can follow droplet formation. Micrographs reproduced from Patel et al (2015).