A guide to membraneless organelles and their various roles in gene regulation
真核細胞には数十種類にのぼる非膜オルガネラが存在し、様々な細胞内現象の場として重要な役割を果たしています。非膜オルガネラは、天然変性タンパク質やRNAを含み、これらの因子間の多価相互作用によって誘発される相分離現象によって形成されることが近年明らかにされました。このメカニズムは、膜を使わずに細胞空間を区画化する機構として大きな注目を集めています。本総説では、まず非膜オルガネラに見られる共通の特徴について概説し、次に10種類もの代表的な非膜オルガネラを取り上げ、それらの構成因子、形成機構、機能についての最新知見について解説しています。特に非膜オルガネラの機能様式から、巨大分子装置形成と遺伝子発現制御という主に2つの機能様式に分類し、一方では細胞特異性やストレス誘導性といった形成条件の観点からも非膜オルガネラを分類して、その共通性や相違点を解説しています。さらには、最近になって現れてきた新しいトピックスである非膜オルガネラ形成におけるRNAの役割、各オルガネラ間に認められるクロストーク、また癌や神経変性疾患といった疾患における非膜オルガネラの役割についても幅広く紹介しています。
Membraneless organelles (MLOs) are detected in cells as dots of mesoscopic size. By undergoing phase separation into a liquid-like or gel-like phase, MLOs contribute to intracellular compartmentalization of specific biological functions. In eukaryotes, dozens of MLOs have been identified, including the nucleolus, Cajal bodies, nuclear speckles, paraspeckles, promyelocytic leukaemia protein (PML) nuclear bodies, nuclear stress bodies, processing bodies (P bodies) and stress granules. MLOs contain specific proteins, of which many possess intrinsically disordered regions (IDRs), and nucleic acids, mainly RNA. Many MLOs contribute to gene regulation by different mechanisms. Through sequestration of specific factors, MLOs promote biochemical reactions by simultaneously concentrating substrates and enzymes, and/or suppressing the activity of the sequestered factors elsewhere in the cell. Other MLOs construct inter-chromosomal hubs by associating with multiple loci, thereby contributing to the biogenesis of macromolecular machineries essential for gene expression, such as ribosomes and spliceosomes. The organization of many MLOs includes layers, which might have different biophysical properties and functions. MLOs are functionally interconnected and are involved in various diseases, prompting the emergence of therapeutics targeting them. In this Review, we introduce MLOs that are relevant to gene regulation and discuss their assembly, internal structure, gene-regulatory roles in transcription, RNA processing and translation, particularly in stress conditions, and their disease relevance.
Authors: Tetsuro Hirose, Kensuke Ninomiya, Shinichi Nakagawa, Tomohiro Yamazaki
Journal: Nature Reviews Molecular Cell Biology(2022)
DOI: https://doi.org/10.1038/s41580-022-00558-8