PT  - JOURNAL ARTICLE
AU  - Alexander S. Zhovmer
AU  - Alexis Manning
AU  - Chynna Smith
AU  - Yashavanti Vishweshwarayah
AU  - Jian Wang
AU  - Pablo J. Sáez
AU  - Xufei Ma
AU  - Alexander X. Cartagena-Rivera
AU  - Rakesh K. Singh
AU  - Nikolay V. Dokholyan
AU  - Erdem D. Tabdanov
TI  - Septin-Mediated Mechanobiological Reprogramming of T Cell Transmigration and 3D Motility
AID  - 10.1101/2022.01.18.476840
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.01.18.476840
4099  - http://biorxiv.org/content/early/2022/01/20/2022.01.18.476840.short
4100  - http://biorxiv.org/content/early/2022/01/20/2022.01.18.476840.full
AB  - T cells migrate in nearly every healthy, inflamed or diseased tissue. Such ‘all-terrain’ motility is achieved by a dynamic mechanobiological balance between amoeboid and mesenchymal-like migration modes. Here, we report that septin proteins function as a key regulator of migratory balance in T cells. We show that active septins compartmentalize the lymphocyte’s cortex into a peristaltically treadmilling ‘tube’ during the avoidance response to mechanically crowding hindrances. Cortical peristaltism along segmented T cell mechanically channels nucleus and cytoplasm translocation between mechanically crowding 3D collagen fibers. Septins’ inactivation abruptly shifts T cell motility balance towards mesenchymal-like mode, characterized by distinct contact guidance and MAP4-, SEPT9-, HDAC6- mediated enhancement of microtubules and microtubule-associated dynein contractility. The non-stretchable microtubular cables secure structurally coherent cell passage through confining spaces and long-distance transmission of dynein-generated forces, which effectively replace diminished actomyosin contractility. Thus, septins provide T cells with a structural and signaling molecular switch between actomyosin-driven amoeboid and dynein-driven mesenchymal-like migration.Competing Interest StatementThe authors have declared no competing interest.