Mena regulates nesprin-2 to control actin–nuclear lamina associations, trans-nuclear membrane signalling and gene expression

Frederic Li Mow Chee, Bruno Beernaert, Billie G. C. Griffith, Alexander E. P. Loftus, Yatendra Kumar, Jimi C. Wills, Martin Lee, Jessica Valli, Ann P. Wheeler, J. Douglas Armstrong, Maddy Parsons, Irene M. Leigh, Charlotte M. Proby, Alex Kriegsheim, Wendy A. Bickmore, Margaret C. Frame and Adam Byron ()
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Frederic Li Mow Chee: University of Edinburgh
Bruno Beernaert: University of Edinburgh
Billie G. C. Griffith: University of Edinburgh
Alexander E. P. Loftus: University of Edinburgh
Yatendra Kumar: University of Edinburgh
Jimi C. Wills: University of Edinburgh
Martin Lee: University of Edinburgh
Jessica Valli: Heriot-Watt University
Ann P. Wheeler: University of Edinburgh
J. Douglas Armstrong: University of Edinburgh
Maddy Parsons: King’s College London
Irene M. Leigh: University of Dundee
Charlotte M. Proby: University of Dundee
Alex Kriegsheim: University of Edinburgh
Wendy A. Bickmore: University of Edinburgh
Margaret C. Frame: University of Edinburgh
Adam Byron: University of Edinburgh

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Interactions between cells and the extracellular matrix, mediated by integrin adhesion complexes, play key roles in fundamental cellular processes, including the sensing and transduction of mechanical cues. Here, we investigate systems-level changes in the integrin adhesome in patient-derived cutaneous squamous cell carcinoma cells and identify the actin regulatory protein Mena as a key node in the adhesion complex network. Mena is connected within a subnetwork of actin-binding proteins to the LINC complex component nesprin-2, with which it interacts and co-localises at the nuclear envelope. Moreover, Mena potentiates the interactions of nesprin-2 with the actin cytoskeleton and the nuclear lamina. CRISPR-mediated Mena depletion causes altered nuclear morphology, reduces tyrosine phosphorylation of the nuclear membrane protein emerin and downregulates expression of the immunomodulatory gene PTX3 via the recruitment of its enhancer to the nuclear periphery. We uncover an unexpected role for Mena at the nuclear membrane, where it controls nuclear architecture, chromatin repositioning and gene expression. Our findings identify an adhesion protein that regulates gene transcription via direct signalling across the nuclear envelope.

Date: 2023
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DOI: 10.1038/s41467-023-37021-x

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