Extracellular signals induce dynamic ER remodeling through αTAT1-dependent microtubule acetylation

Hannah R. Ortiz, Paola Cruz Flores, Julia Podgorski, Aaron Ramonett, Tasmia Ahmed, Nadine Hempel, Pascale G. Charest, Nathan A. Ellis, Paul R. Langlais, William R. Montfort, Karthikeyan Mythreye, Sanjay Kumar, Nam Y. Lee

Research output: Contribution to journalArticlepeer-review

Abstract

Dynamic changes in the endoplasmic reticulum (ER) morphology are central to maintaining cellular homeostasis. Microtubules (MT) facilitate the continuous remodeling of the ER network into sheets and tubules by coordinating with many ER-shaping protein complexes, although how this process is controlled by extracellular signals remains unknown. Here we report that TAK1, a kinase responsive to various growth factors and cytokines including TGF-β and TNF-α, triggers ER tubulation by activating αTAT1, an MT-acetylating enzyme that enhances ER-sliding. We show that this TAK1/αTAT1-dependent ER remodeling promotes cell survival by actively downregulating BOK, an ER membrane-associated proapoptotic effector. While BOK is normally protected from degradation when complexed with IP3R, it is rapidly degraded upon their dissociation during the ER sheets-to-tubules conversion. These findings demonstrate a distinct mechanism of ligand-induced ER remodeling and suggest that the TAK1/αTAT1 pathway may be a key target in ER stress and dysfunction.

Original languageEnglish (US)
Article number101003
JournalNeoplasia (United States)
Volume53
DOIs
StatePublished - Jul 2024

Keywords

  • Alpha TAT1
  • BOK
  • Endoplasmic reticulum
  • Microtubules
  • TAK1
  • TGF-beta

ASJC Scopus subject areas

  • Cancer Research

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