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Primary cilia and the reciprocal activation of AKT and SMAD2/3 regulate stretch-induced autophagy in trabecular meshwork cells.

Publication ,  Journal Article
Shim, MS; Nettesheim, A; Dixon, A; Liton, PB
Published in: Proc Natl Acad Sci U S A
March 30, 2021

Activation of autophagy is one of the responses elicited by high intraocular pressure (IOP) and mechanical stretch in trabecular meshwork (TM) cells. However, the mechanosensor and the molecular mechanisms by which autophagy is induced by mechanical stretch in these or other cell types is largely unknown. Here, we have investigated the mechanosensor and downstream signaling pathway that regulate cyclic mechanical stretch (CMS)-induced autophagy in TM cells. We report that primary cilia act as a mechanosensor for CMS-induced autophagy and identified a cross-regulatory talk between AKT1 and noncanonical SMAD2/3 signaling as critical components of primary cilia-mediated activation of autophagy by mechanical stretch. Furthermore, we demonstrated the physiological significance of our findings in ex vivo perfused eyes. Removal of primary cilia disrupted the homeostatic IOP compensatory response and prevented the increase in LC3-II protein levels in response to elevated pressure challenge, strongly supporting a role of primary cilia-mediated autophagy in regulating IOP homeostasis.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

March 30, 2021

Volume

118

Issue

13

Location

United States

Related Subject Headings

  • Trabecular Meshwork
  • Time-Lapse Imaging
  • Stress, Mechanical
  • Smad3 Protein
  • Smad2 Protein
  • Proto-Oncogene Proteins c-akt
  • Primary Cell Culture
  • Ocular Hypertension
  • Mechanotransduction, Cellular
  • Intravital Microscopy
 

Citation

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Shim, M. S., Nettesheim, A., Dixon, A., & Liton, P. B. (2021). Primary cilia and the reciprocal activation of AKT and SMAD2/3 regulate stretch-induced autophagy in trabecular meshwork cells. Proc Natl Acad Sci U S A, 118(13). https://doi.org/10.1073/pnas.2021942118
Shim, Myoung Sup, April Nettesheim, Angela Dixon, and Paloma B. Liton. “Primary cilia and the reciprocal activation of AKT and SMAD2/3 regulate stretch-induced autophagy in trabecular meshwork cells.Proc Natl Acad Sci U S A 118, no. 13 (March 30, 2021). https://doi.org/10.1073/pnas.2021942118.
Shim MS, Nettesheim A, Dixon A, Liton PB. Primary cilia and the reciprocal activation of AKT and SMAD2/3 regulate stretch-induced autophagy in trabecular meshwork cells. Proc Natl Acad Sci U S A. 2021 Mar 30;118(13).
Shim, Myoung Sup, et al. “Primary cilia and the reciprocal activation of AKT and SMAD2/3 regulate stretch-induced autophagy in trabecular meshwork cells.Proc Natl Acad Sci U S A, vol. 118, no. 13, Mar. 2021. Pubmed, doi:10.1073/pnas.2021942118.
Shim MS, Nettesheim A, Dixon A, Liton PB. Primary cilia and the reciprocal activation of AKT and SMAD2/3 regulate stretch-induced autophagy in trabecular meshwork cells. Proc Natl Acad Sci U S A. 2021 Mar 30;118(13).
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

March 30, 2021

Volume

118

Issue

13

Location

United States

Related Subject Headings

  • Trabecular Meshwork
  • Time-Lapse Imaging
  • Stress, Mechanical
  • Smad3 Protein
  • Smad2 Protein
  • Proto-Oncogene Proteins c-akt
  • Primary Cell Culture
  • Ocular Hypertension
  • Mechanotransduction, Cellular
  • Intravital Microscopy