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PMID: 21610068 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

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

The Journal of biological chemistry ·Vol. 286 ·No. 27 ·2011-07-08 ·Pages 24426-33

Lu JP, Wang Y, Sliter DA, Pearce MM, Wojcikiewicz RJ

Abstract

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.

MeSH Terms
Animals Endoplasmic Reticulum/genetics,metabolism HeLa Cells Humans Inositol 1,4,5-Trisphosphate Receptors/genetics,metabolism Membrane Proteins/genetics,metabolism Multiprotein Complexes/genetics,metabolism Mutation Nerve Tissue Proteins/genetics,metabolism Proteasome Endopeptidase Complex/genetics,metabolism Protein Binding Protein Structure, Secondary Rats Ubiquitin-Protein Ligases/genetics,metabolism Ubiquitination/physiology
Chemicals
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
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Lu Justine P
Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York 13210, USA.
Wang Yuan
Sliter Danielle A
Pearce Margaret M P
Wojcikiewicz Richard J H
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Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
1083-351X
DOI
10.1074/jbc.M111.251983
Published
2011-07-08
Epub
2011-00-24
Pages
24426-33
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC3129221
Subset
IM
Grants
NIDDK NIH HHS · R01 DK049194 · United States
NIDDK NIH HHS · R29 DK049194 · United States
NIDDK NIH HHS · DK049194 · United States
External Links
PubMed source DOI: 10.1074/jbc.M111.251983 PMC Full Text View journal details
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