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EDEM1 Drives Misfolded Protein Degradation via ERAD and Exploits ER-Phagy as Back-Up Mechanism When ERAD Is Impaired

1
Department of Molecular Cell Biology, Institute of Biochemistry, Splaiul Independentei 296, 060031 Bucharest 17, Romania
2
Department of Bioinformatics & Structural Biochemistry, Institute of Biochemistry, Splaiul Independentei 296, 060031 Bucharest 17, Romania
3
Center for Medical Biochemistry, Max Perutz Labs, Medical University of Vienna, A-1030 Vienna, Austria
*
Author to whom correspondence should be addressed.
These authors contributed equally to this manuscript.
Int. J. Mol. Sci. 2020, 21(10), 3468; https://doi.org/10.3390/ijms21103468
Received: 7 April 2020 / Revised: 30 April 2020 / Accepted: 7 May 2020 / Published: 14 May 2020
(This article belongs to the Section Biochemistry)
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. View Full-Text
Keywords: EDEM1; ERAD; ER-phagy; autophagy; protein quality control; mass spectrometry; protein degradation; endoplasmic reticulum; intrinsically disordered region; EDEM1 interaction network EDEM1; ERAD; ER-phagy; autophagy; protein quality control; mass spectrometry; protein degradation; endoplasmic reticulum; intrinsically disordered region; EDEM1 interaction network
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MDPI and ACS Style

Chiritoiu, M.; Chiritoiu, G.N.; Munteanu, C.V.A.; Pastrama, F.; Ivessa, N.E.; Petrescu, S.M. EDEM1 Drives Misfolded Protein Degradation via ERAD and Exploits ER-Phagy as Back-Up Mechanism When ERAD Is Impaired. Int. J. Mol. Sci. 2020, 21, 3468. https://doi.org/10.3390/ijms21103468

AMA Style

Chiritoiu M, Chiritoiu GN, Munteanu CVA, Pastrama F, Ivessa NE, Petrescu SM. EDEM1 Drives Misfolded Protein Degradation via ERAD and Exploits ER-Phagy as Back-Up Mechanism When ERAD Is Impaired. International Journal of Molecular Sciences. 2020; 21(10):3468. https://doi.org/10.3390/ijms21103468

Chicago/Turabian Style

Chiritoiu, Marioara; Chiritoiu, Gabriela N.; Munteanu, Cristian V.A.; Pastrama, Florin; Ivessa, N. E.; Petrescu, Stefana M. 2020. "EDEM1 Drives Misfolded Protein Degradation via ERAD and Exploits ER-Phagy as Back-Up Mechanism When ERAD Is Impaired" Int. J. Mol. Sci. 21, no. 10: 3468. https://doi.org/10.3390/ijms21103468

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