An Endoplasmic Reticulum (ER) Membrane Complex Composed of SPFH1 and SPFH2 Mediates the ER-associated Degradation of Inositol 1,4,5-Trisphosphate ReceptorsS

How endoplasmic reticulum (ER) proteins that are substrates for the ER-associated degradation (ERAD) pathway are recognized for polyubiquitination and proteasomal degradation is largely unresolved. Inositol 1,4,5-trisphosphate receptors (IP 3 Rs) form tetrameric calcium channels in ER membranes, whose primary role is to control the release of ER calcium stores, but whose levels are also regulated, in an activation-dependent manner, by the ERAD pathway. Here we report that the ER membrane protein SPFH1 and its homolog SPFH2 form a heteromeric ∼2 MDa complex that binds to IP 3 R tetramers immediately after their activation and is required for their processing. The complex is ring-shaped (diameter ∼250Å ), and RNA interference-mediated depletion of SPFH1 and SPFH2 blocks IP 3 R polyubiquitination and degradation. We propose that this novel SPFH1/2 complex is a recognition factor that targets IP 3 Rs and perhaps other substrates for ERAD.