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SPFH1 and SPFH2 form a high molecular weight complex in the ER membrane that mediates the ER‐associated degradation of inositol 1,4,5‐trisphosphate receptors and other substrates in mammalian cells
Author(s) -
Pearce Margaret M.P.,
Wang Yuan,
Wilkens Stephan,
Wojcikiewicz Richard J.H.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.605.5
Subject(s) - endoplasmic reticulum associated protein degradation , endoplasmic reticulum , microbiology and biotechnology , ubiquitin , receptor , chemistry , inositol , unfolded protein response , biology , biochemistry , gene
The endoplasmic reticulum (ER)‐associated degradation (ERAD) pathway is responsible for the degradation of aberrant proteins in the ER and the regulated degradation of several ER resident proteins. Inositol 1,4,5‐trisphosphate receptors (IP 3 Rs) form tetrameric Ca 2+ channels in the ER membrane and are converted from stable proteins into ERAD substrates following their activation by IP 3 and Ca 2+ . Using activated, endogenous IP 3 Rs as a tool, we have recently identified two novel mediators of the mammalian ERAD pathway—SPFH1 and SPFH2 (SPFH domain‐containing protein, members 1 and 2). SPFH1 and SPFH2 associate with IP 3 Rs immediately after their activation but prior to their polyubiquitination, and depletion of either SPFH1 or SPFH2 by RNAi inhibited the ERAD of IP 3 Rs and other mammalian ERAD substrates. SPFH1 and SPFH2, both ER membrane proteins that protrude into the ER lumen, were found to exist exclusively as an ∼1MDa complex by native PAGE, and TEM of purified, endogenous SPFH1/2 complex indicates that it assembles into ring‐like structures. These results suggest that SPFH1 and SPFH2 form a high molecular weight, ring‐shaped complex in the ER membrane that plays a key role in the early steps of mammalian ERAD pathway, perhaps as a factor involved in substrate recognition or retrotranslocation. Sources of funding: NIH, PhRMA Foundation