Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 21, Issue 10, Pages -Publisher
MDPI
DOI: 10.3390/ijms21103468
Keywords
EDEM1; ERAD; ER-phagy; autophagy; protein quality control; mass spectrometry; protein degradation; endoplasmic reticulum; intrinsically disordered region; EDEM1 interaction network
Funding
- UEFISCDI [PN-II-PCE-2012-4-0350, PN-III-P1-1.1-PD- 2016-1528, PN-III-PCCDI-2018-1]
- Romanian Academy
- ESF
- Romanian Government [SOP HRD/107/1.5/S/82514]
- Herzfelder Family Foundation
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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 alpha -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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