Get3 is a holdase chaperone and moves to deposition sites for aggregated proteins when membrane targeting is blocked

TY - JOUR

T1 - Get3 is a holdase chaperone and moves to deposition sites for aggregated proteins when membrane targeting is blocked

AU - Powis, Katie

AU - Schrul, Bianca

AU - Tienson, Heather

AU - Gostimskaya, Irina

AU - Breker, Michal

AU - High, Stephen

AU - Schuldiner, Maya

AU - Jakob, Ursula

AU - Schwappach, Blanche

PY - 2013/1/15

Y1 - 2013/1/15

N2 - The endomembrane system of yeast contains different tail-anchored proteins that are post-translationally targeted to membranes via their C-terminal transmembrane domain. This hydrophobic segment could be hazardous in the cytosol if membrane insertion fails, resulting in the need for energy-dependent chaperoning and the degradation of aggregated tail-anchored proteins. A cascade of GET proteins cooperates in a conserved pathway to accept newly synthesized tail-anchored proteins from ribosomes and guide them to a receptor at the endoplasmic reticulum, where membrane integration takes place. It is, however, unclear how the GET system reacts to conditions of energy depletion that might prevent membrane insertion and hence lead to the accumulation of hydrophobic proteins in the cytosol. Here we show that the ATPase Get3, which accommodates the hydrophobic tail anchor of clients, has a dual function: promoting tail-anchored protein insertion when glucose is abundant and serving as an ATP-independent holdase chaperone during energy depletion. Like the generic chaperones Hsp42, Ssa2, Sis1 and Hsp104, we found that Get3 moves reversibly to deposition sites for protein aggregates, hence supporting the sequestration of tail-anchored proteins under conditions that prevent tail-anchored protein insertion. Our findings support a ubiquitous role for the cytosolic GET complex as a triaging platform involved in cellular proteostasis.

AB - The endomembrane system of yeast contains different tail-anchored proteins that are post-translationally targeted to membranes via their C-terminal transmembrane domain. This hydrophobic segment could be hazardous in the cytosol if membrane insertion fails, resulting in the need for energy-dependent chaperoning and the degradation of aggregated tail-anchored proteins. A cascade of GET proteins cooperates in a conserved pathway to accept newly synthesized tail-anchored proteins from ribosomes and guide them to a receptor at the endoplasmic reticulum, where membrane integration takes place. It is, however, unclear how the GET system reacts to conditions of energy depletion that might prevent membrane insertion and hence lead to the accumulation of hydrophobic proteins in the cytosol. Here we show that the ATPase Get3, which accommodates the hydrophobic tail anchor of clients, has a dual function: promoting tail-anchored protein insertion when glucose is abundant and serving as an ATP-independent holdase chaperone during energy depletion. Like the generic chaperones Hsp42, Ssa2, Sis1 and Hsp104, we found that Get3 moves reversibly to deposition sites for protein aggregates, hence supporting the sequestration of tail-anchored proteins under conditions that prevent tail-anchored protein insertion. Our findings support a ubiquitous role for the cytosolic GET complex as a triaging platform involved in cellular proteostasis.

KW - Adenosine Triphosphatases/metabolism

KW - Carrier Proteins/metabolism

KW - Cell Membrane/metabolism

KW - Guanine Nucleotide Exchange Factors/metabolism

KW - Models, Molecular

KW - Molecular Chaperones/metabolism

KW - Protein Transport

KW - Saccharomyces cerevisiae/metabolism

KW - Saccharomyces cerevisiae Proteins/metabolism

U2 - 10.1242/jcs.112151

DO - 10.1242/jcs.112151

M3 - SCORING: Journal article

C2 - 23203805

VL - 126

SP - 473

EP - 483

JO - J CELL SCI

JF - J CELL SCI

SN - 0021-9533

IS - Pt 2

ER -