p14ARF forms meso-scale assemblies upon phase separation with NPM1

Eric Gibbs, Qi Miao, Mylene Ferrolino, Richa Bajpai, Aila Hassan, Aaron H. Phillips, Aaron Pitre, Rainer Kümmerle, Shondra Miller, Gergely Nagy, Wellington Leite, William Heller, Chris Stanley, Barbara Perrone and Richard Kriwacki ()
Additional contact information
Eric Gibbs: St. Jude Children’s Research Hospital
Qi Miao: St. Jude Children’s Research Hospital
Mylene Ferrolino: St. Jude Children’s Research Hospital
Richa Bajpai: St. Jude Children’s Research Hospital
Aila Hassan: Bruker Switzerland AG
Aaron H. Phillips: St. Jude Children’s Research Hospital
Aaron Pitre: St. Jude Children’s Research Hospital
Rainer Kümmerle: Bruker Switzerland AG
Shondra Miller: St. Jude Children’s Research Hospital
Gergely Nagy: Oak Ridge National Laboratory
Wellington Leite: Oak Ridge National Laboratory
William Heller: Oak Ridge National Laboratory
Chris Stanley: Oak Ridge National Laboratory
Barbara Perrone: Bruker Switzerland AG
Richard Kriwacki: St. Jude Children’s Research Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract NPM1 is an abundant nucleolar chaperone that, in addition to facilitating ribosome biogenesis, contributes to nucleolar stress responses and tumor suppression through its regulation of the p14 Alternative Reading Frame tumor suppressor protein (p14ARF). Oncogenic stress induces p14ARF to inhibit MDM2, stabilize p53 and arrest the cell cycle. Under non-stress conditions, NPM1 stabilizes p14ARF in nucleoli, preventing its degradation and blocking p53 activation. However, the mechanisms underlying the regulation of p14ARF by NPM1 are unclear because the structural features of the p14ARF-NPM1 complex were elusive. Here we show that p14ARF assembles into a gel-like meso-scale network upon phase separation with NPM1. This assembly is mediated by intermolecular contacts formed by hydrophobic residues in an α-helix and β-strands within a partially folded N-terminal portion of p14ARF. These hydrophobic interactions promote phase separation with NPM1, enhance p14ARF nucleolar partitioning, restrict NPM1 diffusion within condensates and nucleoli, and reduce cellular proliferation. Our structural analysis provides insights into the multifaceted chaperone function of NPM1 in nucleoli by mechanistically linking the nucleolar localization of p14ARF to its partial folding and meso-scale assembly upon phase separation with NPM1.

Date: 2024
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DOI: 10.1038/s41467-024-53904-z

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