Putative Protein Interactome of the Rhomboid Protease RHBDL4

The physiological functions of the rhomboid-related protein
4 (RHBDL4)
are emerging, but their molecular details remain unclear. Because
increased expression of RHBDL4 has been clinically linked to poorer
outcomes in cancer patients, this association urgently demands a better
understanding of RHBDL4. To elucidate the molecular interactions and
pathways that RHBDL4 may be involved in, we conducted proximity-dependent
biotin identification (BioID) assays. Our analyses corroborated several
of the expected protein interactors such as the transitional endoplasmic
reticulum (ER) ATPase VCP/p97 (TERA), but they also described novel
putative interactors including IRS4, PGAM5, and GORS2. Using proximity-ligation
assays, we validated VCP/p97, COPB, and VRK2 as proteins that are
in proximity to RHBDL4. Overall, our results support the emerging
functions of RHBDL4 in ER quality control and also point toward putative
RHBDL4 functions in protein membrane insertion and membrane organization
and trafficking.