Hui Jiang’s laboratory reveals a new mechanism of protein quality control at mitochondrial outer membrane

On March 11, 2019, Hui Jiang’s laboratory published a paper titled “Mitochondrial AAA‐ATPase Msp1 detects mislocalized tail‐anchored proteins through a dual‐recognition mechanism” in EMBO reports. This paper reveals how Msp1 detects and removes mislocalized tail-anchored (TA) proteins.

TA proteins contain a C-terminal transmembrane (TM) segment and localize to organelle membranes. Their sorting signals reside in the TM segment and its flanking sequences and are recognized by sorting machineries. It has been known that the GET pathway targets TA proteins to the ER. Dysfunction of the GET pathway causes TA protein mislocalization to mitochondria. These mislocalized TA proteins are subsequently cleared by Msp1, an AAA-ATPase at mitochondrial outer membrane. It remains unclear how Msp1 detects and distinguishes its substrates from authentic mitochondrial TA proteins.

The authors extensively characterized Msp1 and its substrates, including the mitochondrially-targeted Pex1530, and full-length Pex15, which mislocalizes to mitochondria upon dysfunction of Pex19 but not the GET pathway. Moreover, the authors identified two new substrates, Frt1 and Ysy6. The results collectively suggest that mislocalized TA proteins expose hydrophobic surfaces in the cytoplasm and are recognized by Msp1 through conserved hydrophobic residues. Introducing a hydrophobic patch into mitochondrial TA proteins transforms them into Msp1 substrates. In addition, Msp1 substrates Pex1530 and Frt1 contain basic inter-membrane space (IMS) residues critical for their mitochondrial mistargeting. Remarkably, Msp1 recognizes this feature through the acidic D12 residue in its IMS domain. This dual-recognition mechanism involving interactions at the cytoplasmic and IMS domains of Msp1 and substrates greatly facilitates substrate recognition and is required by Msp1 to safeguard mitochondrial functions.

Lanlan Li and Jing Zheng from Jiang lab are co-first authors of the paper. Drs. Xi Wu and Hui Jiang are co-corresponding authors. The work was supported by the Ministry of Science and Technology of China, National Natural Science Foundation of China, Municipal Government of Beijing, China Postdoctoral Science Foundation and Beijing Postdoctoral Research Foundation.