RNF170 protein, an endoplasmic reticulum membrane ubiquitin ligase, mediates inositol 1,4,5-trisphosphate receptor ubiquitination and degradation

J Biol Chem. 2011 Jul 8;286(27):24426-33. doi: 10.1074/jbc.M111.251983. Epub 2011 May 24.


Inositol 1,4,5-trisphosphate (IP(3)) receptors are endoplasmic reticulum membrane calcium channels that, upon activation, are degraded via the ubiquitin-proteasome pathway. While searching for novel mediators of IP(3) receptor processing, we discovered that RNF170, an uncharacterized RING domain-containing protein, associates rapidly with activated IP(3) receptors. RNF170 is predicted to have three membrane-spanning helices, is localized to the ER membrane, and possesses ubiquitin ligase activity. Depletion of endogenous RNF170 by RNA interference inhibited stimulus-induced IP(3) receptor ubiquitination, and degradation and overexpression of a catalytically inactive RNF170 mutant suppressed stimulus-induced IP(3) receptor processing. A substantial proportion of RNF170 is constitutively associated with the erlin1/2 (SPFH1/2) complex, which has been shown previously to bind to IP(3) receptors immediately after their activation. Depletion of RNF170 did not affect the binding of the erlin1/2 complex to stimulated IP(3) receptors, whereas erlin1/2 complex depletion inhibited RNF170 binding. These results suggest a model in which the erlin1/2 complex recruits RNF170 to activated IP(3) receptors where it mediates IP(3) receptor ubiquitination. Thus, RNF170 plays an essential role in IP(3) receptor processing via the ubiquitin-proteasome pathway.

Publication types

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

MeSH terms

  • Animals
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism*
  • HeLa Cells
  • Humans
  • Inositol 1,4,5-Trisphosphate Receptors / genetics
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Mutation
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding
  • Protein Structure, Secondary
  • Rats
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination / physiology*


  • ERLIN1 protein, human
  • ERLIN2 protein, human
  • Inositol 1,4,5-Trisphosphate Receptors
  • Membrane Proteins
  • Multiprotein Complexes
  • Nerve Tissue Proteins
  • RNF170 protein, human
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex