RT Journal Article
SR Electronic
T1 Actin networks modulate heterogenous NF-κB dynamics in response to TNFα
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.01.19.476961
DO 10.1101/2022.01.19.476961
A1 Butera, Francesca
A1 Sero, Julia E.
A1 Dent, Lucas
A1 Bakal, Chris
YR 2022
UL http://biorxiv.org/content/early/2022/01/21/2022.01.19.476961.abstract
AB The canonical NF-κB transcription factor RELA is a master regulator of immune and stress responses and is commonly upregulated in PDAC tumours. Using live imaging, we characterised single cell RELA translocation dynamics in two human PDAC cell lines and identified high cell-to-cell variability in RELA responses to TNFα, including unresponsive, damped, and sustained nuclear RELA localisation. Using a combination of quantitative single cell imaging and Bayesian analysis, we determined that heterogeneity in RELA nuclear translocation between and within PDAC cell lines is dependent on cytoskeletal organisation, in particular actin abundance and distribution. Subsequently, RELA nuclear localisation could be up or downregulated through biochemical modulation of cell shape and the cytoskeleton, particularly by disrupting nucleation of actin stress fibres and branched actin via formin and ARP2/3 inhibition. Together, our data provide evidence that actin configuration regulates RELA translocation during the inflammatory response and that targeting actin dynamics can be used to modulate misregulated NF-κB signalling in PDAC.Competing Interest StatementThe authors have declared no competing interest.