PT  - JOURNAL ARTICLE
AU  - Buer Sen
AU  - Zhihui Xie
AU  - Sean Howard
AU  - Maya Styner
AU  - Andre J van Wijnen
AU  - Gunes Uzer
AU  - Janet Rubin
TI  - Mechanically induced nuclear shuttling of β-catenin requires co-transfer of actin
AID  - 10.1101/2021.11.22.469581
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.11.22.469581
4099  - http://biorxiv.org/content/early/2021/11/22/2021.11.22.469581.short
4100  - http://biorxiv.org/content/early/2021/11/22/2021.11.22.469581.full
AB  - Mesenchymal stem cells (MSC) respond to environmental forces with both cytoskeletal re-structuring and activation of protein chaperones of mechanical information, β-catenin and Yes-Associated Protein 1 (YAP1). To function, MSCs must differentiate between dynamic forces such as cyclic strains of extracellular matrix due to physical activity and static strains due to ECM stiffening. To delineate how MSCs recognize and respond differently to both force types, we compared effects of dynamic (200 cycles x 2%) and static (1 × 2% hold) strain on nuclear translocation of β-catenin and YAP1 at 3h after force application. Dynamic strain induced nuclear accumulation of β-catenin, and increased cytoskeletal actin structure and cell stiffness, but had no effect on nuclear YAP1 levels. Critically, both nuclear actin and nuclear stiffness increased along with dynamic strain-induced β-catenin transport. Augmentation of cytoskeletal structure using either static strain or lysophosphatidic acid (LPA) did not increase nuclear content of β–catenin or actin, but induced robust nuclear increase in YAP1. As actin binds β-catenin, we considered whether β-catenin, which lacks a nuclear localization signal, was dependent on actin to gain entry to the nucleus. Knockdown of cofilin-1 (Cfl1) or importin-9 (Ipo9), which co-mediate nuclear transfer of G-actin, prevented dynamic strain-mediated nuclear transfer of both β-catenin and actin. In sum, dynamic strain induction of actin re-structuring promotes nuclear transport of G-actin, concurrently supporting nuclear access of β-catenin via mechanisms utilized for actin transport. Thus, dynamic and static strain activate alternative mechanoresponses reflected by differences in the cellular distributions of actin, β-catenin and YAP1.Significance statement Cells integrate both static and dynamic mechanical signals through the actin cytoskeleton which is attached to the nuclear envelope, affecting nuclear transport of β-catenin and YAP1. Dynamic strain induces nuclear translocation of β-catenin, but not YAP1, while static strain causes nuclear translocation of YAP1, but not β-catenin. Importantly, nuclear transport of actin is induced by dynamic but not static force. Furthermore, nuclear import of β-catenin depends on cofilin/importin-9 dependent actin transport mechanisms. Thus the presence of β-catenin and YAP1 in the nucleus represent specific responses to regulatory mechanical signals.Competing Interest StatementThe authors have declared no competing interest.RT-qPCRreverse transcriptase real time quantitative polymerase chain reactionGFPgreen fluorescent proteinYFPyellow fluorescent protein