Journal Article

PARylation regulates stress granule dynamics, phase separation, and neurotoxicity of disease-related RNA-binding proteins

Tian Kuili, Gui Xinrui, Du Aiying, Jiang, Hong, Liu, Cong, Zhang, Kai, Gu Jinge, Qian Beituo, Fang Yanshan, Zhang Yaoyang, Ma, Zhiwei, Deng Xue, Sun, Le, Duan Yongjia, Duan Gang, Wang, Chen

2019

Overview

Mutations in RNA-binding proteins (RBPs) localized in ribonucleoprotein (RNP) granules, such as hnRNP A1 and TDP-43, promote aberrant protein aggregation, which is a pathological hallmark of various neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Protein posttranslational modifications (PTMs) are known to regulate RNP granules. In this study, we investigate the function of poly(ADP-ribosyl)ation (PARylation), an important PTM involved in DNA damage repair and cell death, in RNP granule-related neurodegeneration. We reveal that PARylation levels are a major regulator of the assembly-disassembly dynamics of RNP granules containing disease-related RBPs, hnRNP A1 and TDP-43. We find that hnRNP A1 can both be PARylated and bind to PARylated proteins or poly(ADP-ribose) (PAR). We further uncover that PARylation of hnRNP A1 at K298 controls its nucleocytoplasmic transport, whereas PAR-binding via the PAR-binding motif (PBM) of hnRNP A1 regulates its association with stress granules. Moreover, we reveal that PAR not only dramatically enhances the liquid-liquid phase separation of hnRNP A1, but also promotes the co-phase separation of hnRNP A1 and TDP-43 in vitro and their interaction in vivo. Finally, both genetic and pharmacological inhibition of PARP mitigates hnRNP A1- and TDP-43-mediated neurotoxicity in cell and Drosophila models of ALS. Together, our findings suggest a novel and crucial role for PARylation in regulating the dynamics of RNP granules, and that dysregulation in PARylation and PAR levels may contribute to ALS disease pathogenesis by promoting protein aggregation.

• Publisher: Nature Publishing Group
• Subject: Adenosine diphosphate / ADP-ribosylation / Agglomeration / Amyotrophic lateral sclerosis / Binding / Cell culture / Cell death / Dementia disorders / Deoxyribonucleic acid / Disease / Dismantling / DNA / DNA damage / DNA repair / Frontotemporal dementia / Fruit flies / Granular materials / Liquid phases / Mutation / Neurodegeneration / Neurodegenerative diseases / Neurological diseases / Neurotoxicity / Pathogenesis / Pharmacology / Phase separation / Poly(ADP-ribose) / Poly(ADP-ribose) polymerase / Protein interaction / Proteins / Ribonucleic acid / Ribose / RNA / RNA-binding protein