The roles of hnRNP A2/B1 in RNA biology and disease

Advanced Review

Yu Liu, Song‐Lin Shi

Published Online: Jun 26 2020

DOI: 10.1002/wrna.1612

Full article on Wiley Online Library: HTML PDF

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Abstract The RNA‐binding protein hnRNPA2/B1 is a member of the hnRNPs family and is widely expressed in various tissues. hnRNPA2/B1 recognizes and binds specific RNA substrates and DNA motifs and is involved in the transcription, splicing processing, transport, stability, and translation regulation of a variety of RNA molecules and in regulating the expression of a large number of genes. hnRNPA2/B1 is also involved in telomere maintenance and DNA repair, while its expression changes and mutations are involved in the development of various tumors and neurodegenerative and autoimmune diseases. This paper reviews the role and mechanism of hnRNPA2/B1 in RNA metabolism, tumors, and neurodegenerative and autoimmune diseases. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein‐RNA Interactions: Functional Implications RNA in Disease and Development > RNA in Disease

Functional domains of hnRNPA1 and hnRNPA2/B1. The N‐terminal of A1, A2 and B1 proteins contains two RNA recognition motifs (RRM1 and RRM2), and the C‐terminal is a glycine‐rich low‐complexity region (LC) containing an RGG box, M9 nuclear localization signal (NLS), and core prion‐like domain (PrLD). E9 is an amino acid sequence encoded by Exon 9 and deleted by alternative splicing in A2b and B1b isoforms

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Abnormal hnRNPA2/B1 is involved in a variety of diseases. hnRNPA2/B1 is one of the important regulatory proteins of RNA. Abnormal hnRNPA2/B1 alters a variety of cellular life activities, leading to a variety of diseases, including cancers, neurodegenerative and autoimmune diseases. Overexpression of hnRNPA2/B1 promotes multiple malignant phenotypes such as proliferation, metastasis and Warburg effect in a variety of tumor cells, but at least inhibits metastasis in breast cancer cells and lung cancer cells, which reflects the differences in the downstream genes regulated by hnRNPA2/B1 in different tumor cells. In neurodegenerative disease, depletion of A2 affects variable splicing events and gene expression profiles in the brains of AD patients. Mutated hnRNPA2/B1 can cause or affect ALS and/or FTD. As a viral DNA sensor, hnRNPA2/B1 is an important contributor to innate immune defense. hnRNPA2/B1 is also involved in several stages of virus replication. As the target of autoantibodies, the up‐regulation of hnRNPA2/B1 is involved in the pathological process of autoimmune diseases, such as SLE, RA and AIH

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hnRNPA2/B1 regulates the expression and secretion of target RNA molecules at different stages. hnRNPA2/B1 can not only bind to DNA to regulate transcription by small activating dsRNA, but also participate in DNA repair, telomere maintenance and recognition of viral DNA. hnRNPA2/B1 is involved in almost every step of RNA synthesis and processing by binding to a variety of specific sequences on RNA molecules. In the nucleus, hnRNPA2/B1 is involved in transcription, pre‐mRNA splicing, polyadenylation site selection and nuclear transport. In the cytoplasm, hnRNPA2/B1 is involved in A2RE RNA granule assembly, transport, localized translation, mRNA degradation regulation and exosome miRNA sorting. During these processes, the m6A marker may facilitate the binding of A2B1 to specific RNA sequences (Wu et al., 2018). Under the stimulation of cellular stress, hnRNPA2/B1 protein binds RNA with other hnRNPs (such as TDP‐43, FUS) to form transient and dynamic stress particles in the cytoplasm

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