Quality control pathways of tail-anchored proteins

Tail-anchored (TA) proteins have an N-terminal domain in the cytosol and a C-terminal transmembrane domain anchored to a variety of organelle membranes. TA proteins are recognized by targeting factors at the transmembrane domain and C-terminal sequence and are guided to distinct membranes. The promiscuity of targeting sequences and the dysfunction of targeting pathways cause mistargeting of TA proteins. TA proteins are under surveillance by quality control pathways. For resident TA proteins at mitochondrial and ER membranes, intrinsic instability or stimuli induced degrons of the cytosolic and transmembrane domains are sensed by quality control factors to initiate degradation of TA proteins. These pathways are summarized as TA protein degradation-Cytosol (TAD-C) and TAD-Membrane (TAD-M) pathways. For mistargeted and a subset of solitary TA proteins at mitochondrial and peroxisomal membranes, a unique pathway has been revealed in recent years. Msp1/ATAD1 is an AAA-ATPase dually-localized to mitochondrial and peroxisomal membranes. It directly recognizes mistargeted and solitary TA proteins and dislocates them out of membrane. Dislocated substrates are subsequently ubiquitinated by the ER-resident Doa10 ubiquitin E3 ligase complex for degradation. We summarize and discuss the substrate recognition, dislocation and degradation mechanisms of the Msp1 pathway.