# A multivalent adaptor mechanism drives the nuclear import of proteasomes

## TL;DR

The paper explains how proteasomes are imported into the nucleus using a multivalent adaptor called AKIRIN2, which helps transport large complexes through the nuclear pore.

## Contribution

The study reveals AKIRIN2 as a multivalent scaffold coordinating proteasome import via multiple importins.

## Key findings

- AKIRIN2 binds multiple importins and the 20S proteasome to coordinate nuclear import.
- RanGTP triggers importin release and AKIRIN2 degradation in the nucleus.
- AKIRIN2's multivalency enables proteasome transport despite nuclear pore size limitations.

## Abstract

Nuclear protein homeostasis, including transcription factor turnover, critically depends on the nuclear proteasomes that must be imported after cell division. This dynamic process requires AKIRIN2, a small unstructured protein whose mechanistic role has remained elusive despite its essential function. Using an integrated approach combining protein-wide saturation mutagenesis screens, cryo-EM, and biochemical reconstitution, we characterize AKIRIN2 as a scaffold protein that coordinates the assembly of an importin cluster around the proteasome. AKIRIN2 binds in multiple copies to the 20S proteasome and simultaneously interacts with importin IPO9 and the KPNA2/KPNB1 heterodimer. In the nucleus, RanGTP triggers importin dissociation, releasing the proteasome, while AKIRIN2 undergoes ubiquitin-independent degradation. Our findings reveal how AKIRIN2’s multivalency facilitates the recruitment of multiple importins to the proteasome, a critical adaptation for transporting this large macromolecular complex into the nucleus and maintaining the nuclear proteome.

Nuclear protein homeostasis relies on proteasome import into the nucleus. Here the authors identify how assembled human proteasomes are transported across the nuclear pore complex and reveal a mechanism enabling the large complex to bypass pore size limitations.