IRE1α-XBP1 is a novel branch in the transcriptional regulation of Ucp1 in brown adipocytes

The unfolded protein response (UPR) not only resolves endoplasmic reticulum (ER) stress, but also regulates cellular physiological functions. In this study, we first linked the UPR to the physiological roles of brown adipose tissue (BAT). BAT is one of the tissues that control energy homeostasis in the body. Brown adipocytes are able to dissipate energy in the form of heat owing to their mitochondrial protein, uncoupling protein 1 (UCP1). We found that one of the UPR branches, the IRE1α-XBP1 pathway, was activated during the transcriptional induction of Ucp1. Inhibiting the IRE1α-XBP1 pathway reduced the induction of Ucp1 expression. However, the activation of the IRE1α-XBP1 pathway by ER stress never upregulated Ucp1. On the other hand, the activation of protein kinase A (PKA) induced Ucp1 transcription through the activation of IRE1α-XBP1. The inhibition of PKA abrogated the activation of IRE1α-XBP1 pathway, while the inhibition of a p38 mitogen activated protein kinase (p38 MAPK), which is one of the downstream molecules of PKA, never suppressed the activation of IRE1α-XBP1 pathway. These data indicate that PKA-dependent IRE1α-XBP1 activation is crucial for the transcriptional induction of Ucp1 in brown adipocytes and they demonstrate a novel, ER stress -independent role of the UPR during thermogenesis.

• Publication year

  2015

• Venue

  Scientific Reports

• Publication date

  2015-11-16

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/srep16580PMID 26568450PMCID 4644985
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• Protein kinase A drives Ucp1 transcription through IRE1α-XBP1, and p38 MAPK inhibition does not block IRE1α-XBP1 activation.

  Confidence 0.97

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• Inhibiting IRE1α-XBP1 reduces Ucp1 induction, whereas ER stress-driven activation of the same pathway does not increase Ucp1 expression.

  Confidence 0.95

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• IRE1α-XBP1 pathway is activated during the transcriptional induction of Ucp1 in brown adipocytes.

  Confidence 0.98

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review

• brown adipocytes

  cell type

  Thermogenic adipocytes found in brown adipose tissue that specialize in heat production.

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• endoplasmic reticulum stress

  stress response

  Cellular stress caused by disrupted protein folding or load in the endoplasmic reticulum.

  Aliases: ER stress

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• ire1α-xbp1 pathway

  pathway

  A branch of the unfolded protein response centered on IRE1α-mediated XBP1 signaling.

  Aliases: IRE1α-XBP1, IRE1alpha-XBP1

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• p38 mapk

  kinase

  A stress-activated mitogen-activated protein kinase involved in signaling downstream of multiple stimuli.

  Aliases: p38 mitogen activated protein kinase

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• protein kinase a

  kinase

  A cAMP-dependent serine/threonine kinase used in intracellular signaling cascades.

  Aliases: PKA

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• ucp1

  gene, protein

  The mitochondrial uncoupling protein 1 gene and its protein product expressed in brown adipocytes.

  Aliases: uncoupling protein 1

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• unfolded protein response

  stress response

  A cellular signaling network that responds to endoplasmic reticulum stress.

  Aliases: UPR

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review

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