Sustained induction of collagen synthesis by TGF-β requires regulated intramembrane proteolysis of CREB3L1

PLoS One. 2014 Oct 13;9(10):e108528. doi: 10.1371/journal.pone.0108528. eCollection 2014.


CREB3L1 (cAMP response element binding protein 3-like 1), a transcription factor synthesized as a membrane-bound precursor and activated through Regulated Intramembrane Proteolysis (RIP), is essential for collagen production by osteoblasts during bone development. Here, we show that TGF-β (transforming growth factor-β), a cytokine known to stimulate production of collagen during wound healing and fibrotic diseases, induces proteolytic activation of CREB3L1 in human A549 cells. This activation results from inhibition of expression of TM4SF20 (transmembrane 4 L6 family member 20), which normally inhibits RIP of CREB3L1. Cleavage of CREB3L1 releases its NH2-terminal domain from membranes, allowing it to enter the nucleus where it binds to Smad4 to activate transcription of genes encoding proteins required for assembly of collagen-containing extracellular matrix. Our findings raise the possibility that inhibition of RIP of CREB3L1 could prevent excess deposition of collagen in certain fibrotic diseases.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Collagen / biosynthesis*
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Extracellular Matrix / metabolism*
  • Humans
  • Nerve Tissue Proteins / metabolism*
  • Proteolysis / drug effects*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Smad4 Protein / metabolism
  • Transforming Growth Factor beta / pharmacology*


  • CREB3L1 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • Nerve Tissue Proteins
  • Smad4 Protein
  • Transforming Growth Factor beta
  • Collagen