A revised model of nuclear actin import: Importin 9 competes with cofilin, profilin, and RanGTP for actin binding.

Keplinger AJ, Srinivasan PA, Christensen SM, Suarez C, Ruthenburg AJ

The Journal of biological chemistry30 Dec 2025

PMID41478570PMCIDPMC12860355DOI10.1016/j.jbc.2025.111123PepBankPUB-41478570

Summary

While predominantly studied in cytoplasmic contexts, actin plays critical roles in the nucleus, regulating genome accessibility, transcription, and DNA repair. Cell-based studies have contributed to a widely accepted model in which the import factor importin 9 (IPO9) acts in concert with the actin filament-severing protein cofilin to transport actin into the nucleus. The classical nuclear localization signal on cofilin is thought to anchor IPO9 to cofilin-bound actin monomers, driving the formation of an import-competent tripartite actin-cofilin-IPO9 complex. Contrary to this established model of actin import, we demonstrate that IPO9 directly binds to monomeric actin with midnanomolar affinity and, rather than promoting IPO9-actin complex formation, cofilin competitively inhibits the binding of IPO9 to actin. To define the mechanism of IPO9 binding, we subject monomeric actin to competitive IPO9 binding in the presence of well-established actin-binding molecules and find proteins that engage either the barbed face, profilin, or pointed face, DNase I, competitively limit IPO9-actin complex formation, whereas sterically less demanding binding partners, thymosin beta-4 and latrunculin B, do not. Consistent with these findings, we demonstrate that IPO9 modestly decreases the rate of actin filament assembly, a process that requires both actin faces, and that IPO9 exhibits minimal binding to actin filaments. Finally, we identify unexpected affinity between the nuclear import release factor RanGTP and monomeric actin; however, a tripartite IPO9-actin-RanGTP complex does not form. The competitive interactions observed between IPO9 and cytoplasmic actin-binding proteins suggest that dynamically coupled equilibria mediate the nuclear transport of actin monomers.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study1

No result from this study comes from a test of the peptide.

Studies that did not test the peptide alone1

In this study, Thymosin beta-4 (human) was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking Thymosin beta-4 (human).

01LabNot a test of Thymosin beta-4 (human) aloneIn vitro (cell-free)Mechanism
In competitive binding experiments with monomeric actin, thymosin beta‑4 did not competitively limit formation of the importin 9-actin complex.
In plain wordsIn lab tests, thymosin beta‑4 did not block importin 9 from binding actin.
Peptide
Thymosin beta-4 (human)
Outcome
No significant changeEffect of Tβ4 on IPO9-actin complex formation
Study
n: not reported in source
Outcome group
Receptor activity and mechanism · Pharmacology
Source sentences
Summary
whereas sterically less demanding binding partners, thymosin beta-4 and latrunculin B, do not.
In this study, Thymosin beta-4 (human) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Thymosin beta-4 (human).
Show in the study text Report a problemFND-4147857001

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Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
13 Oct 2026, 01:52 UTC
Study results updated
Version 1
12 Oct 2026, 18:17 UTC
First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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