1. Academic Validation
  2. Baseline Unfolded Protein Response Signaling Adjusts the Timing of the Mammalian Cell Cycle

Baseline Unfolded Protein Response Signaling Adjusts the Timing of the Mammalian Cell Cycle

  • Mol Biol Cell. 2024 Apr 24:mbcE23110419. doi: 10.1091/mbc.E23-11-0419.
Soham P Chowdhury 1 Sabrina C Solley 1 Elena Polishchuk 2 Julien Bacal 1 Julia E Conrad 3 Brooke M Gardner 1 Diego Acosta-Alvear 1 Francesca Zappa 1
Affiliations

Affiliations

  • 1 Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA, 93106, USA.
  • 2 Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Naples, Italy.
  • 3 Altos Labs Bay Area Institute of Science, Altos Labs, Inc., Redwood City, CA, 94065, USA.
Abstract

The endoplasmic reticulum (ER) is a single-copy organelle that cannot be generated de novo, suggesting coordination between the mechanisms overseeing ER integrity and those controlling the cell cycle to maintain organelle inheritance. The Unfolded Protein Response (UPR) is a conserved signaling network that regulates ER homeostasis. Here, we show that pharmacological and genetic inhibition of the UPR sensors IRE1, ATF6, and PERK in unstressed cells delays the cell cycle, with PERK inhibition showing the most penetrant effect, which was associated with a slowdown of the G1-to-S/G2 transition. Treatment with the small molecule ISRIB to bypass the effects of PERK-dependent phosphorylation of the translation initiation factor eIF2⍺ had no such effect, suggesting that cell cycle timing depends on PERK's kinase activity but is independent of eIF2⍺ phosphorylation. Using complementary LIGHT and electron microscopy and flow cytometry-based analyses, we also demonstrate that the ER enlarges before mitosis. Together, our results suggest coordination between UPR signaling and the cell cycle to maintain ER physiology during cell division.

Figures
Products