ER Stress-Induced Sphingosine-1-Phosphate Lyase Phosphorylation Potentiates the Mitochondrial Unfolded Protein Response

Asli D. Yildirim, Mevlut Citir, Asli E. Dogan, Zehra Veli, Zehra Yildirim, Ozlem Tufanli, Alexis Traynor-Kaplan, Carsten Schultz, Ebru Erbay

Research output: Contribution to journalArticlepeer-review


The unfolded protein response (UPR) is an elaborate signaling network that evolved to maintain proteostasis in the endoplasmic reticulum (ER) and mitochondria (mt). These organelles are functionally and physically associated, and consequently, their stress responses are often intertwined. It is unclear how these two adaptive stress responses are coordinated during ER stress. The inositol-requiring enzyme-1 (IRE1), a central ER stress sensor and proximal regulator of the UPRER, harbors dual kinase and endoribonuclease (RNase) activities. IRE1 RNase activity initiates the transcriptional layer of the UPRER, but IRE1’s kinase substrate(s) and their functions are largely unknown. Here, we discovered that sphingosine 1-phosphate (S1P) lyase (SPL), the enzyme that degrades S1P, is a substrate for the mammalian IRE1 kinase. Our data show that IRE1-dependent SPL phosphorylation inhibits SPL’s enzymatic activity, resulting in increased intracellular S1P levels. S1P has previously been shown to induce the activation of mitochondrial UPR (UPRmt) in nematodes. We determined that IRE1 kinase-dependent S1P induction during ER stress potentiates UPRmt signaling in mammalian cells. Phosphorylation of eukaryotic translation initiation factor 2α (eif2α) is recognized as a critical molecular event for UPRmt activation in mammalian cells. Our data further demonstrate that inhibition of the IRE1-SPL axis abrogates the activation of two eif2α kinases, namely double-stranded RNA-activated protein kinase (PKR) and PKR–like ER kinase upon ER stress. These findings show that the IRE1-SPL axis plays a central role in coordinating the adaptive responses of ER and mitochondria to ER stress in mammalian cells.

Original languageEnglish (US)
Article number100279
JournalJournal of lipid research
Issue number10
StatePublished - Oct 2022
Externally publishedYes


  • adaptive stress response
  • endoplasmic reticulum
  • endoribonuclease
  • eukaryotic translation initiation factor 2α
  • inositol-requiring enzyme-1
  • ire1-spl axis
  • kinase
  • mitochondria
  • proteostasis
  • signaling networks

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology


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