Phase separation of RNA-binding proteins in physiology and disease: An introduction to the JBC Reviews thematic series

James Shorter

doi:10.1074/jbc.rev119.007944

Abstract

In recent years, there has been a jarring awakening that liquid-liquid phase separation (LLPS) of key protein and nucleic acid scaffolds underpins the biogenesis of diverse membraneless organelles, including P granules and stress granules in the cytoplasm and nucleoli and paraspeckles in the nucleus. These biomolecular condensates are proposed to be critical organizers of subcellular biochemistry and to control the flow of information from genotype to phenotype. Despite clear biological utility, LLPS can also have deleterious outcomes. Phase-separated compartments can concentrate specific RNA-binding proteins (RBPs), such as TDP-43 and fused in sarcoma (FUS), that through low-complexity, prion-like domains have an intrinsic tendency to form self-templating fibrils that are closely tied to fatal neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. This series of reviews illuminates the molecular language underlying membraneless organelle biogenesis, how prion-like domains and post-translational modifications regulate phase behavior, how cells exploit the phase-separation process for adaptive modalities, and how phase separation is corrupted in neurodegenerative diseases. Collectively, these pieces provide a cutting-edge view of our functional and mechanistic understanding of phase separation in physiology and disease.

Highlights

In recent years, there has been a jarring awakening that liquid–liquid phase separation (LLPS) of key protein and nucleic acid scaffolds underpins the biogenesis of diverse membraneless organelles, including P granules and stress granules in the cytoplasm and nucleoli and paraspeckles in the nucleus
Liquid droplets that form at the wrong time or in the wrong place can be detrimental
liquid– liquid phase separation (LLPS) can concentrate certain RNA-binding proteins (RBPs), including TDP-43, fused in sarcoma (FUS), ataxin 2, hnRNPA1, and hnRNPA2. These RBPs contain low-complexity, prion-like domains that can spontaneously morph into self-templating, amyloid-like fibrils. These self-templating fibrils may have beneficial properties in defined contexts, they are primarily linked with devastating neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia

Summary

Introduction

There has been a jarring awakening that liquid–liquid phase separation (LLPS) of key protein and nucleic acid scaffolds underpins the biogenesis of diverse membraneless organelles, including P granules and stress granules in the cytoplasm and nucleoli and paraspeckles in the nucleus. This article is part of the thematic series, Phase separation of RNA-binding proteins in physiology and disease. 2 The abbreviations used are: LLPS, liquid–liquid phase separation; RBP, RNAbinding protein; FUS, fused in sarcoma; ALS, amyotrophic lateral sclerosis; PTM, post-translational modification. These self-templating fibrils may have beneficial properties in defined contexts, they are primarily linked with devastating neurodegenerative diseases, including ALS and frontotemporal dementia.

Results

Conclusion