Control of condensates dictates nucleolar architecture

doi:10.1126/science.abj8350

GSTDTAP > 气候变化

DOI	10.1126/science.abj8350
	Control of condensates dictates nucleolar architecture
	Tomohiro Yamazaki; Tetsuro Hirose
	2021-07-30
发表期刊	Science
出版年	2021
英文摘要	Intracellular organelles that lack a membrane boundary are often formed through liquid-liquid phase separation. The biophysical properties of such structures are linked to their physiological functions and involvement in diseases. Most of these organelles contain RNA molecules that associate with RNA binding proteins (RBPs) to control intracellular phase separation ([ 1 ][1]). Specific long noncoding RNAs (lncRNAs) are especially important in the architecture of membraneless organelles ([ 2 ][2]). On page 547 of this issue, Wu et al. ([ 3 ][3]) provide a mechanistic understanding of how lncRNAs modulate the biophysical properties of phase-separated nucleolar subdomains of the nucleus, where ribosome biogenesis takes place. The nucleolus is the largest membraneless subnuclear organelle and serves as a location for ribosome production, a critical determinant of protein synthesis capacity. It comprises multilayered phase-separated subdomains that possess distinct biophysical properties: fibrillar centers (FCs) that contain the tandemly repeated ribosomal RNA (rRNA) gene cluster [or ribosomal DNA (rDNA)]; the dense fibrillar component (DFC) that surrounds FCs; and the granular component (GC) that includes dozens of FC/DFC units ([ 4 ][4]). The organized multilayered structure of the nucleolus is thought to ensure efficient ribosome biogenesis. This is initiated by rDNA transcription by RNA polymerase I (Pol I) to generate pre-rRNA at the border between the FC and DFC, subsequent pre-rRNA processing in the DFC, and later events, including ribonucleo-protein (RNP) assembly into the ribosomal subunits in the GC. Wu et al. focused on a human-specific nucleolar lncRNA called SLERT (a box H/ACA small nucleolar RNA–ended long noncoding RNA that enhances pre-rRNA transcription) that is located in the DFC. The importance of SLERT was noted by the reduced size and liquidity of the FC/DFC in the absence of the lncRNA ([ 5 ][5]). SLERT associates with the nucleolar RNA helicase DDX21 (DExD-box helicase 21), which regulates transcription by Pol I ([ 5 ][5]). Through in vitro reconstitution and in vivo experiments, Wu et al. demonstrate a role of DDX21 in the architecture and biophysical properties of the FC/DFC and in the regulation of Pol I–mediated transcription. The authors also show how SLERT modulates two distinct DDX21 functions. ![Figure][6] Dynamic subnucleolar condensates The long noncoding RNA (lncRNA) SLERT and RNA helicase DDX21 control the liquidity of dense fibrillar components (DFCs) in the nucleolus and the transcription of ribosomal DNA. Different RNAs can build or dissolve phase-separated regions in the nucleus. GRAPHIC: V. ALTOUNIAN/ SCIENCE DDX21 can adopt open and closed conformations, each with molecular interactions that assemble condensates with distinct biophysical properties. Intermolecular interactions between the open conformation form multimers that assemble less-dynamic condensates in vitro and shrunken FC/DFCs in vivo. By contrast, closed-conformation DDX21, formed through intramolecular interaction between its amino- and carboxyl-terminal domains, is not multimeric and assembles dynamic liquid droplets in vitro and enlarged loose DFCs in vivo. Wu et al. observed that the RNA domain (loop 3) of SLERT directly associates with DDX21 to generate the closed conformation (see the figure). This may disrupt DDX21 interaction with fibrillarin protein, thereby making the DFC structure loose and dynamic. This environment may better accommodate pre-rRNA processing in the DFC. In another mode of action, SLERT prevents DDX21 from hijacking rDNA, thereby enhancing its transcription by Pol I. Wu et al. used single-molecule total internal reflection fluorescent microscopy to monitor the wrapping of rDNA around DDX21 clusters, which prevents Pol I from binding to rDNA. This wrapping is achieved by conformational change of DDX21 to the closed form, which binds rDNA poorly. It is noteworthy that the conformational change is triggered by SLERT but not by rDNA. Mechanistically, SLERT plays a molecular chaperone–like function, whereby its transient binding to DDX21 enables it to induce a conformational change in DDX21 at a substoichiometric level relative to DDX21. Only a few lncRNAs have been studied with respect to how their domains dictate function. SLERT 's binding sites for DDX21 and its mode of binding to produce the closed conformation remain to be elucidated. However, another lncRNA stimulates a similar conformational change of an RBP called FUS (fused in sarcoma) ([ 6 ][7]), indicating a general mode of lncRNA action. A structural approach to visualize the SLERT loop 3–DDX21 interaction could advance mechanistic understanding of lncRNA-mediated conformational switching of regulatory proteins and also reveal the detailed mechanism of the chaperone-like function of SLERT . More broadly, RNAs, as highly negatively charged long biopolymers, nonspecifically prevent intracellular condensation when at high concentrations, and longer RNAs can even dissociate condensates ([ 7 ][8], [ 8 ][9]). However, a number of lncRNAs, including SLERT , can promote or modulate intracellular condensation ([ 9 ][10]–[ 11 ][11]). Each lncRNA assembles a functional RNP complex with a certain set of RBPs that confers the distinct biophysical properties of the condensates. For example, the lncRNA NEAT1 (nuclear paraspeckle assembly transcript 1) binds specific RBPs to assemble membraneless nuclear paraspeckles through micellization, a type of phase separation ([ 9 ][10], [ 12 ][12]). Because SLERT also assembles its own RNP complex with a set of RBPs ([ 5 ][5]), further characterization of the RNP components will help to reveal the details of how SLERT RNP plays a chaperone function in DFCs. SLERT is transcribed by RNA polymerase II (Pol II) and matures through an unusual small nucleolar RNA processing pathway ([ 5 ][5]). Various other lncRNAs transcribed by Pol II also control nucleolar ribosome biogenesis ([ 13 ][13]–[ 15 ][14]), suggesting unexpected roles of lncRNAs in phase-separated nucleolar functions. Given that the nucleolus also plays various regulatory roles under certain physiological and pathological conditions, lncRNAs may control responses to thermal stress, aging, and cancer by modulating the phase-separated structures within the nucleolus. 1. [↵][15]1. S. Alberti, 2. A. A. Hyman , Nat. Rev. Mol. Cell Biol. 22, 196 (2021). [OpenUrl][16][CrossRef][17] 2. [↵][18]1. T. Yamazaki, 2. S. Nakagawa, 3. T. Hirose , Cold Spring Harb. Symp. Quant. 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领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/335528
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Tomohiro Yamazaki,Tetsuro Hirose. Control of condensates dictates nucleolar architecture[J]. Science,2021.
APA	Tomohiro Yamazaki,&Tetsuro Hirose.(2021).Control of condensates dictates nucleolar architecture.Science.
MLA	Tomohiro Yamazaki,et al."Control of condensates dictates nucleolar architecture".Science (2021).