A Novel Receptor-Mediated Nuclear Protein Import Pathway

TLDR

Nuclear protein targeting normally relies on classical NLSs interacting with importin receptors, and hnRNP A1, which may export mRNA, suggests transportin could also mediate this process. The study sought to identify the receptor responsible for M9‑mediated nuclear import. Transportin, a 90‑kDa protein related to importin β, binds wild‑type M9 but not defective mutants and mediates the import of M9‑containing proteins independently of the classical NLS pathway. We discovered that the 38‑amino‑acid M9 signal directs bidirectional nuclear import via a transportin receptor distinct from the classical importin pathway, and that transportin binds M9 and mediates import of M9‑containing proteins, revealing a second receptor‑mediated nuclear import route.

Abstract

Targeting of most nuclear proteins to the cell nucleus is initiated by interaction between the classical nuclear localization signals (NLSs) contained within them and the importin NLS receptor complex. We have recently delineated a novel 38 amino acid transport signal in the hnRNP A1 protein, termed M9, which confers bidirectional transport across the nuclear envelope. We show here that M9-mediated nuclear import occurs by a novel pathway that is independent of the well-characterized, importin-mediated classical NLS pathway. Additionally, we have identified a specific M9-interacting protein, termed transportin, which binds to wild-type M9 but not to transport-defective M9 mutants. Transportin is a 90 kDa protein, distantly related to importin β, and we show that it mediates the nuclear import of M9-containing proteins. These findings demonstrate that there are at least two receptor-mediated nuclear protein import pathways. Furthermore, as hnRNP A1 likely participates in mRNA export, it raises the possibility that transportin is a mediator of this process as well.