Abstract
The endoplasmic reticulum (ER) plays a central role in the biogenesis of most membrane proteins. Among these are proteins localized to the surface of lipid droplets (LDs), fat storage organelles delimited by a phospholipid monolayer. The LD monolayer is often continuous with the membrane of the ER allowing certain membrane proteins to diffuse between the two organelles. In these connected organelles, how some proteins concentrate specifically at the surface of LDs is not known. Here, we show that the ERAD ubiquitin ligase Doa10 controls the levels of some LD proteins. Their degradation is dependent on the localization to the ER and appears independent of the folding state. Moreover, we show that by degrading the ER pool of these LD proteins, ERAD contributes to restrict their localization to LDs. The signals for LD targeting and Doa10‐mediated degradation overlap, indicating that these are competing events. This spatial control of protein localization is a novel function of ERAD that might contribute to generate functional diversity in a continuous membrane system.
Highlights
The endoplasmic reticulum (ER) plays a central role in the biogenesis of membrane and secretory proteins, facilitating the folding and the post-translational modifications necessary for their function (Braakman & Hebert, 2013)
We uncover a new class of substrates of the ERAD ubiquitin ligase Doa10
By degrading the ER pool, ERAD restricts their localization to lipid droplets (LDs), thereby contributing to maintain the individual membrane identities of the ER and LDs
Summary
The endoplasmic reticulum (ER) plays a central role in the biogenesis of membrane and secretory proteins, facilitating the folding and the post-translational modifications necessary for their function (Braakman & Hebert, 2013). Protein folding in the ER is under the surveillance of stringent quality control and polypeptides failing to acquire the native structure are eliminated by ER-associated degradation (or ERAD) (Smith et al, 2011; Christianson & Ye, 2014; Ruggiano et al, 2014). This process involves the recognition of a substrate, its ubiquitination by an ER ubiquitin ligase, membrane extraction facilitated by the cytoplasmic Cdc ATPase, and delivery to the proteasome for degradation. The Asi complex degrades ER proteins mistargeted to the INM, suggesting that ERAD integrates spatial cues
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