title: hnRNPA1 autoregulates its own mRNA expression to remain non-cytotoxic.
abstract: Heterogeneous nuclear ribonucleoprotein (hnRNP)A1, a member of the hnRNP family, is involved in a variety of RNA metabolisms. The hnRNPA1 expression is altered in some human diseases and mutations of the hnRNPA1 gene cause amyotrophic lateral sclerosis and multisystem proteinopathy. It has been therefore assumed that the dysregulation of hnRNPA1 is linked to the pathogenesis of the diseases. However, the mechanism underlying the regulation of the hnRNPA1 expression remains unknown. In this study, using cell-based models, we have found that hnRNPA1 negatively regulates its own mRNA expression by inhibiting the intron10 splicing of hnRNPA1 pre-mRNA. This mechanism likely serves as an autoregulation of the hnRNPA1 expression. We have also found that a low-grade excess of hnRNPA1 expression causes cytotoxicity by activating the mitochondrial apoptosis pathway. Collectively, these data suggest that the level of hnRNPA1 is strictly controlled to be within a certain range by the mRNA autoregulation in the physiological condition so that the cytotoxicity-causative alteration of hnRNPA1 expression does not take place.
authors.affiliation: Department of Pharmacology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-Ku, Tokyo, 160-8402, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Pharmacology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-Ku, Tokyo, 160-8402, Japan. sakimatu@tokyo-med.ac.jp.|Department of Dermatological Neuroscience, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-Ku, Tokyo, 160-8402, Japan. sakimatu@tokyo-med.ac.jp.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Matsuoka
mesh_terms: D002460:Cell Line; D005786:Gene Expression Regulation / Q000502:physiology*; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D012326:RNA Splicing / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D012333:RNA, Messenger; C000619656:hnRNPA1 protein, human
keywords: Autoregulation; Cell death; Splicing; hnRNPA1