Congrats to Soham for his MBoC paper!
Soham and co. observed that cell cycle progress depends on PERK activity, but not eIF2alpha signaling, suggesting a novel signaling output of PERK kinase activity.
Significance Statement
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Blocking the UPR sensors in unstressed cells affects cell cycle dynamics.
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PERK has cell cycle roles that are independent of phosphorylating eIF2α.
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The endoplasmic reticulum expands during the mammalian cell cycle.
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.
