A GUARDIAN FACTOR THAT PROTECTS FOLDING POLYPEPTIDES FROM PROMISCUOUS DEGRADATION

Abstract

Unstructured newly synthesized polypeptides engage with molecular chaperones for correct folding. Meanwhile, the same chaperones actively target misfolded proteins for degradation. Paradoxically, the structure of protein folding intermediates resembles misfolded proteins, and both are chaperones associated. How cells safeguard normal protein folding while eliminating aberrant folding failures is still obscure. In a genetic screen for ER dysfunction mutants, we identified a conserved ER protein complex formed by Slp1 and Emp65. Losing the complex aberrantly accelerate ER-associated degradation (ERAD). Importantly, metabolic labeling reveal that a significant fraction of the newly synthesized proteins that could normally fold are promiscuously degraded in the mutants. Only newly synthesized proteins are destabilized as folded proteins remain stable. Mechanistic analysis suggests that Slp1 transiently binds to pre-mature polypeptides to regulate their accessibility to ERAD. Taken together, we propose that the Slp1-Emp65 complex function as a “guardian” that dedicatedly protects actively folding secretory proteins from promiscuous degradation.