More than one third of all proteins synthesised on cytosolic ribosomes have to be transported across or inserted into subcellular membrane systems. Tail-anchored (TA) proteins are a class of membrane proteins characterised by a single hydrophobic transmembrane domain at their C-terminus, which necessitates shielding of this region as they are targeted to the appropriate organelle. During delivery to the endoplasmic reticulum (ER), the BAG6 complex coordinates the handover of TA proteins from an SGTA-bound preloading complex to the ER delivery component TRC40. Now, with an unbiased proximity-based protein-protein interaction screen, Stephen High and colleagues (Roboti et al., 2022) identify the mitochondrial TA protein MAVS as a client of both SGTA and BAG6 complexes, suggesting that the SGTA–BAG6 quality control system is not specific to TAs solely destined for the ER. With a series of careful co-immunoprecipitation assays, the authors reveal that the BAG6 complex binds to a cytosolic pool of MAVS before it is misinserted into the ER membrane via a pathway involving the ER membrane protein complex (EMC) transmembrane domain insertase, instead of the canonical TRC40 route; after this step, MAVS may be redirected from the ER to the outer mitochondrial membrane. Finally, the authors show that the BAG6-associated pool of MAVS responds to mock viral infection and thus might play a role in coordinating the innate immune response. Together, this work highlights the diversity of pathways facilitating TA protein targeting and provides a novel link between the BAG6 complex and immune signalling.
