STEF/TIAM2-mediated Rac1 activity at the nuclear envelope regulates the perinuclear actin cap

• Published in: Nature communications 2018-05, Vol.9 (1), p.2124-15, Article 2124
• Main Authors: Woroniuk, Anna, Porter, Andrew, White, Gavin, Newman, Daniel T., Diamantopoulou, Zoi, Waring, Thomas, Rooney, Claire, Strathdee, Douglas, Marston, Daniel J., Hahn, Klaus M., Sansom, Owen J., Zech, Tobias, Malliri, Angeliki
• Format: Article
• Language: English
• Subjects: 13/106; 14/1; 14/19; 14/3; 14/35; 14/63; 631/80/386/1700; 631/80/84/2341; 631/80/85; 82/80; A549 Cells; Actin; Actin Capping Proteins - metabolism; Acyltransferases; Animals; Cables; Cancer; Cell Line, Tumor; Chlorocebus aethiops; Cloning; COS Cells; CRISPR; Cytoskeleton; Depletion; Gene expression; Guanine; Guanine nucleotide exchange factor; Guanine Nucleotide Exchange Factors - metabolism; Humanities and Social Sciences; Humans; Localization; Medical research; Mice; Mice, Knockout; Microfilament Proteins - metabolism; Morphology; multidisciplinary; Muscles; Myosin; Nerve Tissue Proteins - metabolism; Nonmuscle Myosin Type IIB - metabolism; Nuclear Envelope - metabolism; Nuclear Proteins - metabolism; Phenotypes; Proteins; rac1 GTP-Binding Protein - metabolism; Rac1 protein; Science; Science (multidisciplinary); Stiffness; Transcription Factors - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-04404-4

The perinuclear actin cap is an important cytoskeletal structure that regulates nuclear morphology and re-orientation during front-rear polarisation. The mechanisms regulating the actin cap are currently poorly understood. Here, we demonstrate that STEF/TIAM2, a Rac1 selective guanine nucleotide exchange factor, localises at the nuclear envelope, co-localising with the key perinuclear proteins Nesprin-2G and Non-muscle myosin IIB (NMMIIB), where it regulates perinuclear Rac1 activity. We show that STEF depletion reduces apical perinuclear actin cables (a phenotype rescued by targeting active Rac1 to the nuclear envelope), increases nuclear height and impairs nuclear re-orientation. STEF down-regulation also reduces perinuclear pMLC and decreases myosin-generated tension at the nuclear envelope, suggesting that STEF-mediated Rac1 activity regulates NMMIIB activity to promote stabilisation of the perinuclear actin cap. Finally, STEF depletion decreases nuclear stiffness and reduces expression of TAZ-regulated genes, indicating an alteration in mechanosensing pathways as a consequence of disruption of the actin cap. The perinuclear actin cap determines nuclear morphology but its regulation is currently poorly understood. Here, the authors find that an activator of the Rac1 GTPase, STEF/TIAM2, localises to the nuclear envelope and contributes to perinuclear actin and myosin tension, which in turn regulates the actin cap.