Importin alpha-mediated nuclear import of cytoplasmic poly(A) binding protein occurs as a direct consequence of cytoplasmic mRNA depletion

TitleImportin alpha-mediated nuclear import of cytoplasmic poly(A) binding protein occurs as a direct consequence of cytoplasmic mRNA depletion
Publication TypeJournal Article
Year of Publication2011
AuthorsKumar RG, Shum L, Glaunsinger BA
JournalMolecular and cellular biology
Volume31
Issue15
Pagination3113-25
Date Published2011 Aug
ISSN1098-5549
KeywordsActive Transport, Cell Nucleus, alpha Karyopherins, Animals, Cell Nucleus, Cercopithecus aethiops, COS Cells, Cytoplasm, Gene Expression Regulation, HEK293 Cells, HeLa Cells, Herpesvirus 1, Human, Humans, Immunoprecipitation, Plasmids, Poly(A)-Binding Protein I, Protein Biosynthesis, RNA, Messenger, Viral Proteins
AbstractRecent studies have found the cytoplasmic poly(A) binding protein (PABPC) to have opposing effects on gene expression when concentrated in the cytoplasm versus in the nucleus. PABPC is predominantly cytoplasmic at steady state, where it enhances protein synthesis through simultaneous interactions with mRNA and translation factors. However, it accumulates dramatically within the nucleus in response to various pathogenic and nonpathogenic stresses, leading to an inhibition of mRNA export. The molecular events that trigger relocalization of PABPC and the mechanisms by which it translocates into the nucleus to block gene expression are not understood. Here, we reveal an RNA-based mechanism of retaining PABPC in the cytoplasm. Expression either of viral proteins that promote mRNA turnover or of a cytoplasmic deadenylase drives nuclear relocalization of PABPC in a manner dependent on the PABPC RNA recognition motifs (RRMs). Using multiple independent binding sites within its RRMs, PABPC interacts with importin α, a component of the classical import pathway. Finally, we demonstrate that the direct association of PABPC with importin α is antagonized by the presence of poly(A) RNA, supporting a model in which RNA binding masks nuclear import signals within the PABPC RRMs, thereby ensuring efficient cytoplasmic retention of this protein in normal cells. These findings further suggest that cells must carefully calibrate the ratio of PABPC to mRNA, as events that offset this balance can dramatically influence gene expression.
DOI10.1128/MCB.05402-11
Alternate JournalMol. Cell. Biol.