VAPB interacts with novel FFAT-like proteins, FAF1 and ASNA1. (A) The FFAT-like motif of FAF1 mediates its interaction with the MSP domain of VAPB and recruits FAF1/p97 to the ER membrane. Similarly, the FFAT-like sequence in ASNA1 mediates VAPB interaction with the TRC complex. (B) RPN2 is a common ubiquitinated target for FAF1 and VAPB. We propose that, on one side, FAF1 protects ubiquitinated RPN2 from deubiquitinating enzymes (DUBs) and other ubiquitin receptors and, on the other side, it recruits p97 hexamers that are necessary for extracting misfolded or misassembled RPN2 from the ER membrane, to allow for its proteasome-mediated degradation. (C) ASNA1 mediates VAPB interaction with a subset of ubiquitinated targets that interact with FAF1 via their ubiquitin chains. We propose that VAPB might represent an alternative receptor for TRCs that are implicated in clearing mislocalized ER proteins.