An ER surface retrieval pathway safeguards the import of mitochondrial membrane proteins in yeast

Abstract

The majority of organellar proteins are translated on cytosolic ribosomes and must be sorted correctly to function. Targeting routes have been identified for organelles such as peroxisomes and the endoplasmic reticulum (ER). However, little is known about the initial steps of targeting of mitochondrial proteins. In this study, we used a genome-wide screen in yeast and identified factors critical for the intracellular sorting of the mitochondrial inner membrane protein Oxa1. The screen uncovered an unexpected path, termed ER-SURF, for targeting of mitochondrial membrane proteins. This pathway retrieves mitochondrial proteins from the ER surface and reroutes them to mitochondria with the aid of the ER-localized chaperone Djp1. Hence, cells use the expanse of the ER surfaces as a fail-safe to maximize productive mitochondrial protein targeting.

Mitochondrial stress-dependent regulation of cellular protein synthesis

“…Recently, an unexpected pathway of targeting mitochondrial membrane proteins, termed ER-surface mediated protein targeting (ER-SURF), was discovered in yeast (Hansen et al, 2018). ER-SURF helps to retrieve mitochondrial proteins from the ER surface and transfers them to mitochondria (Fig.…”

“…This is promoted by the ER-localized chaperone Djp1 that cooperates with the mitochondrial pre-protein receptors Tom70 and Tom71 in this process. Through ER-SURF, Djp1 imports the inner membrane protein Oxa1 (in a precursor and import-competent state) into mitochondria (Hansen et al, 2018). Various mechanisms protect cells from proteotoxic stress induced by the accumulation of precursor proteins in the cytosol, including the stabilization of precursor proteins by cytosolic chaperones and ubiquilins (Itakura et al, 2016;Young et al, 2003), and the proteasomal degradation of over-accumulated proteins (Wrobel et al, 2015).…”

“…Various mechanisms protect cells from proteotoxic stress induced by the accumulation of precursor proteins in the cytosol, including the stabilization of precursor proteins by cytosolic chaperones and ubiquilins (Itakura et al, 2016;Young et al, 2003), and the proteasomal degradation of over-accumulated proteins (Wrobel et al, 2015). Alternative import pathways could have similar protective roles, in which localized translation and ER-SURF appear to be routes mainly for inner membrane proteins (Hansen et al, 2018;Williams et al, 2014). Because of the presence of hydrophobic transmembrane domains (TMDs) and signal sequences, inner membrane proteins are prone to aggregate in the cytosol or be erroneously integrated into other membranes.…”

Recognition and Degradation of Mislocalized Proteins in Health and Disease

“…Whether ubiquitin ligases are involved and at what step they act to mediate Msp1-mediated degradation is not known. Mistargeted proteins can also be rescued, as exemplified by a pathway from the ER to mitochondria involving the chaperone Djp1 (Hansen et al 2018). Misloc.…”

“…Recently, it was shown that some mitochondrial membrane proteins mistargeted to the ER membrane are not degraded, but rather retrieved for successful import into mitochondria (Hansen et al 2018). An ER-localized factor called Djp1 is required for this retrieval pathway.…”