Slp1-Emp65: A Guardian Factor that Protects Folding Polypeptides from Promiscuous Degradation

Abstract

Newly synthesized proteins engage molecular chaperones that assist folding. Their progress is monitored by quality control systems that target folding errors for degradation. Paradoxically, chaperones that promote folding also direct unfolded polypeptides for degradation. Hence, a mechanism was previously hypothesized that prevents the degradation of actively folding polypeptides. In this study, we show that a conserved endoplasmic reticulum (ER) membrane protein complex, consisting of Slp1 and Emp65 proteins, performs this function in the ER lumen. The complex binds unfolded proteins and protects them from degradation during folding. In its absence, approximately 20%-30% of newly synthesized proteins that could otherwise fold are degraded. Although the Slp1-Emp65 complex hosts a broad range of clients, it is specific for soluble proteins. Taken together, these studies demonstrate the vulnerability of newly translated, actively folding polypeptides and the discovery of a new proteostasis functional class we term "guardian" that protects them from degradation.

Protein quality control in the secretory pathway

“…In principle, this provides time for proteins to fold, but this delay may also present folding intermediates to the ERAD machinery, especially since some chaperones are involved in protein folding and turnover (Preston and Brodsky, 2017). This conundrum was solved by the discovery of the Slp1-Emp65 complex, which protects folding intermediates from premature degradation in yeast (Sun and Brodsky, 2017;Zhang et al, 2017).…”

Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway

“…Although PfCARL appears essential 19 , mutations in pfcarl confer resistance to unrelated compounds 24,25 and resistance-conferring mutations in pfcarl are located in transmembrane regions and not in an obvious catalytic site. PfCARL, although conserved in evolution, remains understudied, but its yeast ortholog, Emp65 (Endoplasmic Reticulum Membrane Protein 65) protects folding polypeptides from promiscuous degradation 26 . Mutations in all three parasite proteins may lead to slower rates of protein folding, processing, and sorting.…”

Regulation of inner nuclear membrane associated protein degradation

“…Due to the high rate of protein synthesis at the ER, an assortment of regulatory factors is present to ensure proper folding and modification of nascent proteins [18]. Proteins that fail to fold properly, are not correctly modified, or are in excess of their proper stoichiometry are subject to protein quality control through the ERAD pathway [19,20].…”