Mechanosensitive calcium flashes promote sustained RhoA activation during tight junction remodeling

Saranyaraajan Varadarajan, Shahana A. Chumki, Rachel Stephenson, Eileen R. Misterovich, Jessica L. Wu, Claire E. Dudley, Ivan Erofeev, Andrew B. Goryachev, Ann L. Miller

Research output: Contribution to journalArticlepeer-review

Abstract

Epithelial cell-cell junctions remodel in response to mechanical stimuli to maintain barrier func-tion. Previously, we found that local leaks in tight junctions (TJs) are rapidly repaired by local, transient RhoA activation, termed “Rho flares”, but how Rho flares are regulated is unknown. Here, we discovered intracellular calcium flashes and junction elongation are early events in the Rho flare pathway. Both laser-induced and naturally-occurring TJ breaks lead to local calcium flashes at the site of leaks. Additionally, junction elongation induced by optogenetics increases Rho flare frequency, suggesting Rho flares are mechanically triggered. Depletion of intracellular calcium or inhibition of mechanosensitive calcium channels (MSCs) reduces the amplitude of cal-cium flashes and diminishes the sustained activation of Rho flares. MSC-dependent calcium in-flux is necessary to maintain global barrier function by regulating reinforcement of local TJ pro-teins via junction contraction. Collectively, we uncovered a novel role for MSC-dependent calcium flashes in TJ remodeling, allowing epithelial cells to repair local leaks induced by mechanical stimuli.
Original languageEnglish
Article numbere202105107
Number of pages28
JournalJournal of Cell Biology
Volume221
Issue number4
Early online date7 Mar 2022
DOIs
Publication statusE-pub ahead of print - 7 Mar 2022

Keywords

  • calcium signaling
  • mechanotransduction
  • mechanosensitive calcium channel
  • active RhoA
  • Optogenetics
  • ZO-1
  • tight junctions
  • epithelial barrier function
  • Xenopus laevis
  • cell shape changes
  • junction elongation
  • junction contraction

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