Lipid Droplets Are Essential for Efficient Clearance of Cytosolic Inclusion Bodies

• A microscopic screen in yeast uncovers 13 inclusion body resident proteins
• Iml2, an inclusion resident, is crucial for efficient clearance of inclusion bodies
• Iml2’s interactors reveal a role for lipid droplets in inclusion clearance
• Lipid droplets produce a sterol derivative that assists in inclusion clearance

SummaryExposing cells to folding stress causes a subset of their proteins to misfold and accumulate in inclusion bodies (IBs). IB formation and clearance are both active processes, but little is known about their mechanism. To shed light on this issue, we performed a screen with over 4,000 fluorescently tagged yeast proteins for co-localization with a model misfolded protein that marks IBs during folding stress. We identified 13 proteins that co-localize to IBs. Remarkably, one of these IB proteins, the uncharacterized and conserved protein Iml2, exhibited strong physical interactions with lipid droplet (LD) proteins. Indeed, we here show that IBs and LDs are spatially and functionally linked. We further demonstrate a mechanism for IB clearance via a sterol-based metabolite emanating from LDs. Our findings therefore uncover a function for Iml2 and LDs in regulating a critical stage of cellular proteostasis.