Adipocytes secrete fatty acid binding protein 4, which influences glucose production in hepatocytes and insulin secretion in pancreatic β-cells, but the mechanisms of its secretion are unclear. Villeneuve et al. show that FABP4 is secreted unconventionally through enclosure within endosomes and secretory lysosomes.
Highlights d PERK pathway is required for the production of mIL-1b from proIL-1b d Loss of GRASP55 causes mIL-1b aggregation and affects mIL-1b secretion d IRE1a inhibition causes aggregation of mIL-1b and reduces mIL-1b secretion d GRASP55 controls IRE1a activity in LPS-stimulated macrophages
Endoplasmic reticulum (ER)-associated degradation (ERAD) is the main mechanism of targeting ER proteins for degradation to maintain homeostasis, and perturbations of ERAD lead to pathological conditions. ER-degradation enhancing α-mannosidase-like (EDEM1) was proposed to extract terminally misfolded proteins from the calnexin folding cycle and target them for degradation by ERAD. Here, using mass-spectrometry and biochemical methods, we show that EDEM1 is found in auto-regulatory complexes with ERAD components. Moreover, the N-terminal disordered region of EDEM1 mediates protein–protein interaction with misfolded proteins, whilst the absence of this domain significantly impairs their degradation. We also determined that overexpression of EDEM1 can induce degradation, even when proteasomal activity is severely impaired, by promoting the formation of aggregates, which can be further degraded by autophagy. Therefore, we propose that EDEM1 maintains ER homeostasis and mediates ERAD client degradation via autophagy when either dislocation or proteasomal degradation are impaired.
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